Cyclin-dependent kinase 4 degraders

Abstract

The present disclosure relates to pyrrolo-pyrimidine compounds, or pharmaceutically acceptable salts thereof, of Formula (I): Compounds of the disclosure are useful for degrading cyclin-dependent kinase 4 (CDK4), and methods of making the same are provided.

Description

Attorney Ref. No. 01234-0009-00PCTCYCLIN-DEPENDENT KINASE 4 DEGRADERSBACKGROUND

[0001] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and it is the selective activation of specific CDKs allows tor the proper ordering of the steps in cell cycle progression. Cyclins and their binding partner CDKs are key regulatory enzymes driving the cell cycle and cell proliferation. The catalytic activities of CDKs are regulated by their interactions with cyclins (including cyclin A, cyclin B, D-type cyclins, and cyclins E), and with CDK inhibitors (Ding, L. et al., Int. J. Mol. Sci. (2020) 21(6): 1960). In mammals there is one mitotic CDK (CDK1) and multiple interphase CDKs, including CDK2, CDK4, and CDK6.

[0002] Cyclin DI is an important cell cycle regulator that activates CDK4 / 6. CDK4 and closely related CDK6 play key roles in mammalian cell proliferation, where they help to drive the progression of cells into the DNA synthetic (S) phase of the cell-division. The enzymatic activities of CDK4 and CDK6 in the first gap phase (Gl) of the cycle are governed by D-type cyclins expressed in response to various extracellular signals, including stimulatory mitogens (Sherr, C. J. etal., Cancer Discov. (2016) Cancer Disc. 6(4): 353-367)). Upon activation, CDK4 / 6 phosphorylate the retinoblastomas tumor suppressor protein (Rb), leading to the release of its repression on the transcription factor E2F1, which is then free to induce the expression of proteins involved in Gl to S phase transition. This fluctuation in cyclin expression results in the oscillation in CDK activity and the tightly regulated cell cycle. In cancer cells, the cell cycle is often dysregulated, and such cells then develop dependencies on individual cyclins or CDKs, such as CDK4 or CDK6, providing opportunities for therapeutic targeting (Suski, J. M. et al., Cancer Cell (2021) 39(6): 759-778).

[0003] Given multiple nodes of oncogenic signals converge on cyclin D-CDK4 / 6 in multiple cancer types, particularly breast cancers, CDK4 / 6 thus have been targeted by small molecule inhibitors for cancer therapy. There are three Cyclin D isoforms, but only Cyclin DI is required for the maintenance of ER+ breast cancer cell lines. Targeted overexpression of cyclin DI in mammary glands of transgenic mice led to development of mammary carcinomas (Wang, T. C. et al., Nature (1994) 369: 6482), while induced deletion of cyclin DI in adult mice with ErbB2-driven breast cancer halted tumor growth in vivo (Choi, Y. J. et al., Cancer Cell (2012) 22(4): 438-451). CDK4 / 6 inhibitors are established therapeutics for hormone receptor positive (HR+) / human epidermal growth factor receptor-2 negative (HER2-) breast cancers (Goel, S. etAttorney Ref. No. 01234-0009-00PCTal., Nat. Rev. Cancer (2022) 22(6): 356-372; Sherr, C. J. et al., Cancer Discov. (2016) Cancer Disc. 6(4): 353-367). In fact, CDK4 / 6 inhibitors have revolutionized the treatment of hormonepositive metastatic breast cancers (mBCs), and they are currently established as standard therapies in combination with endocrine therapy as first- and second-line systemic treatment options for both endocrine-sensitive and endocrine-resistant mBC patients (Asghar, U. S. et al., JCO Precis. Oncol. (2022) 6: e210002). Although CDK4 / 6 inhibitors have significant clinical benefits and enable physicians to delay starting chemotherapy, they are associated with severe side effects (Asghar (2022); Braal. C. L. et al., Drugs (2021) 81(3): 317-331). Frequently observed side effects include hematological abnormalities including reduced numbers of neutrophils, erythroid cells and platelets that are associated with anemia, bleeding and a higher risk of infections (Braal (2021)). Recapitulated with these clinical side effects, inducible deletion of CDK6 in adult mice hematopoiesis was accompanied by neutropenia, while that was not the case in the induced deletion of CDK4 (Maurer, B. et al., Haematologica (2021) 106(10): 2624-2632). Thus, anti-CDK4 therapies by sparing CDK6 may reduce dose-limiting hematologica adverse events, and maximize CDK4 target coverage in HR+HER- breast cancer, which may allow a completely block aberrant Gl-S phase transition and tumor growth.

[0004] However, the effects of CDK4 / 6 inhibitors are limited by intrinsic or acquired resistance to CDK4 / 6 inhibitors, and almost all patients progress after treatment (Yuan, K. et al., ActaPharm. Sin. B (2021) 11(1): 30-54, Epub 2000). Multiple mechanisms of resistance to CDK4 / 6 inhibitors have been previously identified, including loss of Rb and amplification and / or overexpression of pl 6, CDK6, cyclin DI, and cyclin E, where activation of the cyclin E-CDK2 pathway compensates for CDK4 / 6 inhibition via a bypass mechanism. Cell line models that rendered resistance to palbociblib demonstrated amplification of the CDK6 locus or increased CDK6 mRNA / protein level, while knockdown of CDK6 restored sensitivity to CDK4 / 6 inhibition, indicating that drug resistance was attributable to increased levels of CDK6 activity (Schoninger, S. F. and Blain, S. W., Mol. Cancer Ther. (2020) 19(1): 3-12; Yang, C. et al., Oncogene (2017) 36: 2255-2264). Recent research has identified the aberrant activation of cyclin E / CDK2 as key mechanism by which tumors can evade CDK4 / 6 blockade(Freeman-Cook, K. et al., Cancer Cell (2021) 39: 1404-1421; Wang, B. et al., Front. Oncol. (2021) 11: 405).

[0005] Targeted protein degradation (TPD) has emerged recently as an attractive novel therapeutic approach, due to the potential benefits including improved selectivity and catalytic nature hence less stringent requirement on exposure compared to traditional small-molecule inhibitors (Bekes, M. et al., Nat. Rev. Drug Discov. (2022) 21(3): 181-200). HeterobifunctionalAttorney Ref. No. 01234-0009-00PCTdegraders, or proteolysis-targeting chimeras (PROTAC), are a commonly used therapeutic modality to achieve targeted protein degradation (Lai, A. C. and Crews, C. M., Nat. Rev. Drug Discov. (2017) 16(2): 101-114). PROTACs are bifunctional degraders that include 2 binding moieties, i.e. the warheads and the E3 ubiquitin ligase-binding moieties. The warheads bind to the target protein of interest with high affinity. The E3 ubiquitin ligase-binding moieties recruit E3 ligases that ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The two ligands are connected by linkers of various flavors.

[0006] No CDK4 or CDK6 degrader has been approved by FDA so far. Intriguingly, CDK4 alone, but not CDK6, is required for the maintenance of ER+ breast cancer cell lines in DepMap. Despite the importance of cyclin DI in cancers, it is largely dispensable for normal physiology as mice deficient in cyclin DI were viable with minor and restricted developmental defects (Choi, Y. J. et al., Cancer Cell (2012) 22(4): 438-451; Fantl, V. et al., Genes & Dev. (1995) 9(19): 2364-2372) suggesting that degradation or inhibition of cyclin DI may be well-tolerated in patients. Xiong has reported degradation of cyclin DI via a bridged PROTAC that recruits the CDK4 / 6-cyclin DI complex by binding cyclin Dl’s partner with a CDK4 / 6 targeting ligand (Xiong, Y. et a!., J. Am. Chem. Soc. (2022) 144(49): 22622-22632).

[0007] Therefore, there is an unmet medical need to develop new CDK4-specific degraders for cancer patients that may have better efficacy by degrading CDK4 or cyclin DI via CDK4-binding while avoiding CDK6 mediated heme toxicity.SUMMARY

[0008] Disclosed herein are compounds of Formula (I), methods of making the same, and methods of treating a disease or disorder mediated by CDK4.

[0009] The present disclosure relates to compounds of Formula (I):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 4 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl, and 3- to 12-membered heterocyclyl optionally substituted onAttorney Ref. No. 01234-0009-00PCTa ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, -(C(Ra2)2)P-C*(=O)-, - (C(Ra2)2)P- N(Rd2)C*(=O)-, and -(C(Ra2)2)P-C(=O)N*(Rd2)- wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is selected from a covalent bond, -(C(Ra3)2)P-, -O-, and -C(=O)-;X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb3, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4;L3is selected from a covalent bond, -O-, and -(C(Ra4)2)P-; orL3is -C2-C4alkynyl-, provided that X2is a covalent bond or X1- L2- X2form a 5- to 12- membered spiroheterocyclyl or a 6- to 12-membered fused heterocyclyl; orL3is selected from -*0-(C(Rel)2)q-C(=0)- and -*N(Rd5)-(C(Rel)2)q-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond; or X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd6; orX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd7;Ring B is selected from:Attorney Ref. No. 01234-0009-00PCTY1is selected from NRd9and -*N(Rd9)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R4is selected from H, D, and Ci-C4alkyl;Y2is C(Re)2 or C(=O);W is CH or N;Ral, Ra2, Ra3, and Ra4are each independently selected from H, D, halo, OH, Ci-C4alkyl, Ci- C4alkoxy, and monocyclic C3-C6 cycloalkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic Cs-Cecycloalkyl, or two Rblattached to the same atom, form a =0;Rb2, Rb3, Rb4, and Rb5are each independently selected from D, halo, OH, CN, and Ci-C4alkyl, or two Rb2, Rb3, Rb4, or Rb5attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, OH, CN, and Ci-C4alkyl;Rc3are each independently selected from H, D, halo, OH, CN, and Ci-C4alkyl;Rdl, Rd2, Rd3, Rd4, Rd5, Rd6, Rd7, Rd8, Rd9, and Rdl° are each independently selected from H, D, Ci-C4alkyl, and monocyclic Cs-Cecycloalkyl;Relare each independently selected from D, halo, OH, CN, N(Rdl0)2, Ci-C4alkyl, and Ci- C4alkoxy;Rfland Rf2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cgcycloalkyl;Attorney Ref. No. 01234-0009-00PCTm is 0 or 1;n is 0, 1, 2, 3, or 4;p is 0, 1, or 2;q is 0, 1, or 2; andtis 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0010] The present disclosure further relates to compounds of Table I, or pharmaceutically acceptable salts thereof.

[0011] The present disclosure furthermore relates to pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt of a compound of Formula (I):and at least one pharmaceutically acceptable excipient

[0012] The present disclosure also relates to a method of treating a disease or disorder mediated by cyclin-dependent kinase 4 (CDK4), comprising providing to a subject in need thereof a compound of Formula (I):or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTIONDefinitions

[0013] Unless otherwise defined, all terms of art, notations and other scientific terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a difference over what is generally understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodologies by those skilled in the art. Standard techniques may be used for chemical synthesis and chemical analysis. AsAttorney Ref. No. 01234-0009-00PCTappropriate, procedures involving the use of commercially available kits and reagents are generally carried out in accordance with manufacturer-defined protocols and conditions unless otherwise noted.

[0014] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5th Ed., Ed.: Smith, M. B. and March, T, John Wiley & Sons, New York: 2001.

[0015] Unless otherwise indicated, the following terms have the following meanings:

[0016] The term “additional anticancer agent” as used herein refers to any one or more therapeutic agent, other than a compound described herein (e.g., Formulae (I)-(XII), or subformulae thereof), or a pharmaceutically acceptable salt thereof, that is or can be used in the treatment of cancer.

[0017] The terms “administer,” “administering,” “administration,” and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action.

[0018] The expressions “administered in combination with,” “co-administration,” and their grammatical equivalents, refer to administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.

[0019] The term “alkyl” used alone or as part of a larger moiety, such as “alkoxyl” and the like, refers to a saturated aliphatic straight-chain or branched monovalent or bivalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1, 2, 3, or 4 carbon atoms, i.e. Ci-C4alkyl. As used herein, a “Ci-C4alkyl” group means a radical having 1, 2, 3, or 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, 1 -propyl, isopropyl, 1 -butyl, isobutyl, ec-butyl, tert-butyl, and the like. In some embodiments, an alkyl group is an unsaturated alkyl group, also termed an alkenyl or alkynyl group. An “alkenyl” group refers to an alkyl group that contains one or more carbon-carbon double bonds. An “alkynyl” group refers to an alkyl group that contains one or more carbon-carbon triple bonds.

[0020] The term “alkoxy” refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, “Ci-C4alkoxy” includes methoxy, ethoxy, propoxy, and butoxy.Attorney Ref. No. 01234-0009-00PCT

[0021] The term “aryl” refers to a radical of a 6- to 12-membered aromatic hydrocarbon ring system. An aryl group can either be monocyclic (“monocyclic aryl”) or polycyclic (e.g., a fused system (“fused aryl”). Non-limiting examples of aryls include phenyl, cyclooctatetraene, indene, and naphthyl. Substituents may be present on one or more rings in the aryl.Substituents on the aryl do not count towards the number of atoms of the aryl. The aryl itself may be linked to the compound via every suitable position of the ring system.

[0022] The expression “CDK4 degrader” refers to a compound that selectively and catalytically degrades CDK4 over other CDKs and other proteins. Said another way, a CDK4 degrader shows no or low degradation of other CDKs and other proteins. A CDK4 degrader degrades CDK4 to a greater extent (e.g, in terms of DCso value, which can be nanomolar) when compared with the degradation of other CDKs and other proteins. Degradation can be measured using known biochemical assays.

[0023] The term “cell” refers to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0024] The term “contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, “contacting” CDK4, or “contacting” a cell with a compound of the disclosure, includes the administration of a compound of the present disclosure to a subject or patient, such as a human, having CDK4, as well as, for example, introducing a compound of the disclosure into a sample containing a cellular or purified preparation containing CDK4.

[0025] The term “cycloalkyl” refers to a radical of a 3- to 10-membered non-aromatic hydrocarbon ring system. A cycloalkyl group can either be monocyclic (“monocyclic cycloalkyl”) or polycyclic (e.g, a fused system (“fused cycloalkyl”), bridged system (“bridged cycloalkyl”), or spiro system (“spirocycloalkyl”)). When a cycloalkyl group is a polycyclic ring system, said ring system includes at least one non-aromatic ring. Non-limiting examples of monocyclic C3-C10 cycloalkyl include: cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Polycyclic cycloalkyl may include fused, bridged, and / or spirocyclic rings. Non-limiting examples of fused or bridged cycloalkyls include: indanyl, tetrahydronaphthyl, bicyclofl.1.0]butane, bicyclo[2.1.0]pentane, bicyclofl.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclicAttorney Ref. No. 01234-0009-00PCTrings (e.g., spirocyclic bicycle wherein two rings share one ring atom). Non -limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.5]octane, spiro[3.5]nonane, spiro[2.6]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. Substituents may be present on one or more rings in the cycloalkyl. Substituents on the cycloalkyl do not count towards the number of atoms of the cycloalkyl. The cycloalkyl itself may be linked to the compound via every suitable position of the ring system.

[0026] The terms “degrade”, “degrading”, or “degradation” refer to the partial or full breakdown of CDK4 proteins, which reduces or eliminates the biological activity of CDK4, as compared to the amount of that proteins in the absence of the degrader (e.g., before administration of the degrader). In some alternatives, the term “degrade” means a decrease in the levels of CDK4 protein of at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% (e.g., before administration of the degrader or at two different timepoints during treatment with the degrader). In other alternatives, inhibit means a decrease in the levels of CDK2 and / or CDK4 of 5% to 25%, 25% to 50%, 50 to 70%, 75 to 100%. In some embodiments, degrade means a decrease in the levels of CDK4 of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro degradation assays. The DCso value refers to the concentration at which 50% maximal degradation was observed.

[0027] The term “degrader” refers to a compound, or a pharmaceutically acceptable salt thereof, that degrades a target protein.

[0028] The expression “E3 ubiquitin ligase-binding moiety” refers to a chemical group that binds to an E3 ubiquitin ligase.

[0029] The expression “effective amount” refers to an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the disease, condition, or cancer being treated in the subject as compared to a control.

[0030] The term “halo” as used herein refers to halogen and includes chloro, fluoro, bromo and iodo.

[0031] The term “heteroaryl” refers to a radical of a 4- to 12-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. Representative heteroaryl groups include ring systems where each ring comprises a heteroatom and is aromatic, e.g., imidazolyl,Attorney Ref. No. 01234-0009-00PCToxazolyl, thiazolyl, triazolyl, pyrrolyl, furanyl, thiophenyl pyrazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, indoyl, indolizinyl, benzothiophenyl, purinyl, pyrido[4,3-d]pyrimidine, napthyl, naphthyridinyl, quinazolinyl, oxadiazolyl, thiadiazolyl, cinnolinyl, indazyl, and pteridinyl. Substituents may be present on one or more rings in the heteroaryl. Substituents on the heteroaryl do not count towards the number of atoms or heteroatoms of the heteroaryl. The heteroaryl itself may be linked to the compound via every suitable position of the ring system.

[0032] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO), substituted nitrogen, oxygen, and sulfur, including sulfoxide and sulfone (“3-12 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a bicyclic system (“bicyclic heterocyclyl”) or a tricyclic system (“tricyclic heterocyclyl”)). A polycyclic ring system includes fused, bridged, or spiro ring systems. A “fused heterocyclyl” refers to a polycyclic heterocyclyl, wherein two rings share two adjacent ring atoms and the bond between the two common ring atoms. A “spiroheterocyclyl” refers to a polycyclic heterocyclyl, wherein two rings share one carbon atom. When a heterocyclyl group is a polycyclic ring system, said ring system includes at least one non-aromatic ring. Exemplary monocyclic heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like. Heterocyclyl polycyclic ring systems can include heteroatoms in one or more rings in the polycyclic ring system, including polycyclic ring systems having a non-aromatic ring fused to a phenyl or heteroaryl ring. Exemplary polycyclic heterocyclic groups include 2J / -benzo[b][l,4]oxazin-3(4J7)-onyl, isoindolin-l-onyl, isoquinolin-l(2H)-onyl, 3-oxabicyclo[3.1.0] hexanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, tetrahydropyrazolo[l,5-a]pyridinyl, 1,4-oxazepanyl, 5, 6,7,8-tetrahydro-4J / -pyrazolo[l,5-a][l,4]diazepinyl, l,3,7-triazaspiro[4.5]decane-2,4-dionyl, 5, 6,7,8-tetrahydroimidazo[l,5-a]pyrazine, 2,7-diazaspiro[3.5]nonanyl, 2,8-diazaspiro[4.5]decanyl, l,2,3,5-tetrahydropyrrolo[3,4-c]pyrrolyl, 2,6-diazaspiro[3.3]heptanyl, 3,9-diazaspiro[5.5]undecanyl, l,7-diazaspiro[4.4]nonanyl, 2-azaspiro[3.3]heptanyl, 3-azaspiro[5.5]undecanyl, 3-azaspiro[5.5]undec-8-enyl, l-azaspiro[3.3]heptanyl, 1,6-diazaspiro[3.3]heptanyl, isoindolinyl, 2,3-dihydro-lH-benzo[d]imidazolyl, indolinyl,Attorney Ref. No. 01234-0009-00PCTbenzo [d]oxazolyl, 1,2-dihydroisoquinolinyl, and the like. Substituents may be present on one or more rings in the heterocyclyl. Substituents on the heterocyclyl do not count towards the number of atoms or heteroatoms of the heterocyclyl. The heterocyclyl itself may be linked to the compound via every suitable position of the ring system.

[0033] The term “inhibitor” refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of a gene and / or a protein. Consequently, a “CDK4 inhibitor” refers to a compound that has a biological effect to inhibit or significantly reduce or down-regulate the biological activity of CDK4.

[0034] The expression “linker moiety” and “linker” refer to a bivalent chemical moiety that binds (e.g., bridges) two separate entities to one another. As used herein, the terms “linker moiety” and “linker” can refer to a bivalent chemical moiety that is covalently bonded to both the pyridine ring of the targeting ligand of the compounds of the disclosure and ring B of the E3 ubiquitin ligase-binding moiety of the compounds of the disclosure.

[0035] The expression “Peak 1” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation / purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2”.

[0036] The expression “pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms, and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0037] The expression “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” refer to a substance that aids the formulation and / or administration of an active agent to and / or absorption by a subject and can be included in the pharmaceutical compositions of the disclosure without causing a significant adverse toxicological effect on the subject.

[0038] The term “pharmaceutically acceptable salt” refers to a pharmaceutical salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0039] The expression “selective degrader” refers to a “CDK4 degrader” that has the ability to selectively degrade CDK4 over another kinase or to selectively reduce target signaling activity relative to off-target signaling activity, via direct or indirect interaction with the target. In one embodiment, the compounds of the present disclosure are selective CDK4 degraders. InAttorney Ref. No. 01234-0009-00PCTsome embodiments, the compounds of the present disclosure (e.g., compounds of Formula (I) and subformulae) are selective for CDK4 over CDK2, CDK6, and CDK9.

[0040] The term “subject” or “patient” refers to a mammal in need of medical treatment, for example, a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In some embodiments, the patient is an adult human.

[0041] The term “tautomers” refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:H

[0042] As readily understood by one skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism and all tautomers of compounds of Formula (I) are within the scope of the present disclosure.

[0043] The term “treating” or “treatment” refers to obtaining a desired pharmacological and / or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or substantially reducing the extent of the disease, condition or cancer; ameliorating or improving a clinical symptom or indicator associated with the disease, disorder, condition or cancer; delaying, inhibiting or decreasing the likelihood of the progression of the disease, condition or cancer; or decreasing the likelihood of recurrence of the disease, condition or cancer.Compounds of the Disclosure

[0044] Provided herein, among other things, are compounds and compositions that modulate (e.g., by protein degradation) the activity of CDK4.EMBODIMENTS

[0045] The present disclosure relates to compounds of Formula (I):Attorney Ref. No. 01234-0009-00PCT(1) or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 4 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, -(C(Ra2)2)P-C*(=O)-, -(C(Ra2)2)P- N(Rd2)C*(=O)-, and -(C(Ra2)2)P-C(=O)N*(Rd2)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is selected from a covalent bond, -(C(Ra3)2)P-, -O-, and -C(=O)-;X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb3, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4;L3is selected from a covalent bond, -O-, and -(C(Ra4)2)P-; orL3is -C2-C4alkynyl-, provided that X2is a covalent bond or X1- L2- X2form a 5- to 12- membered spiroheterocyclyl or a 6- to 12-membered fused heterocyclyl; orL3is selected from -*0-(C(Rel)2)q-C(=0)- and -*N(Rd5)-(C(Rel)2)q-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond; or X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd6; orAttorney Ref. No. 01234-0009-00PCTX2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd7;Ring B is selected from:Y1is selected from NRd9and -*N(Rd9)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R4is selected from H, D, and Ci-C4alkyl;Y2is C(Re)2 or C(=O);W is CH or N;Ral, Ra2, Ra3, and Ra4are each independently selected from H, D, halo, OH, Ci-C4alkyl, Ci- C4alkoxy, and monocyclic C3-C6 cycloalkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic Cs-Cecycloalkyl, or two Rblattached to the same atom, form a =0;Rb2, Rb3, Rb4, and Rb5are each independently selected from D, halo, OH, CN, and Ci-C4alkyl, or two Rb2, Rb3, Rb4, or Rb5attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, OH, CN, and Ci-C4alkyl;Rc3are each independently selected from H, D, halo, OH, CN, and Ci-C4alkyl;Rdl, Rd2, Rd3, Rd4, Rd5, Rd6, Rd7, Rd8, Rd9, and Rdl° are each independently selected from H, D, Ci-C4alkyl, and monocyclic Cs-Cecycloalkyl;Attorney Ref. No. 01234-0009-00PCTRelare each independently selected from D, halo, OH, CN, N(Rdl0)2, Ci-C4alkyl, and Ci- C4alkoxy;Rfland Rf2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; m is 0 or 1;n is 0, 1, 2, 3, or 4;p is 0, 1, or 2;q is 0, 1, or 2; andtis 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0046] In addition to embodiment (1) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(2) (A) R1is H;(B) R1is D;(C) R1is selected from Cialkyl, C2alkyl, C3alkyl, and C4alkyl;(D) R1is Ci-C4alkyl, wherein one or more H in Ci-C4alkyl is replaced by D;(E) R1is CD3.

[0047] In addition to embodiments (1) and (2) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(3) (A) R2is H;(B) R2is D;(C) R2is selected from Cialkyl, C2alkyl, C3alkyl, and C4alkyl;(D) R2is Ci-C4alkyl, wherein one or more H in Ci-C4alkyl is replaced by D;(E) R2is CD3.

[0048] In addition to embodiments (1) through (3) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(4) (A) R3is selected from Cialkyl, C2alkyl, C3alkyl, C4alkyl, Csalkyl, and Cealkyl optionally substituted with 1 to 4 Ral; for example,(B) R3is methyl;(C) R3is C2alkyl optionally substituted with 1 to 3 Ral;(D) R3is C3alkyl optionally substituted with 1 to 4 Ral;(E) R3is C4alkyl optionally substituted with 1 to 4 Ral;(F) R3is Csalkyl optionally substituted with 1 to 4 Ral;Attorney Ref. No. 01234-0009-00PCT(G) R3is Cealkyl optionally substituted with 1 to 4 Ral;(H) R3is Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl; for example, (I) R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;(J) R3is bridged Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl;(K) R3is selected from bridged Cscycloalkyl, bridged Cecycloalkyl, and bridged Cjcycloalkyl, each optionally substituted with 1 to 3 Rbl;(L) R3is bicyclo[2.2.1]hexyl or bicyclo[2.2.1]heptyl;(M) R3is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted with 1 to 2 Rbl;(N) R3is selected from cyclopropyl optionally substituted with 1 to 2 Rbl, cyclobutyl optionally substituted with 1 to 2 Rbl, and cyclopentyl substituted with 1 to 2 Rbl;(O) R3is cyclopropyl optionally substituted with 1 to 2 Rbl;(P) R3is cyclobutyl;(Q) R3is cyclopentyl substituted with 1 to 2 Rbl;(R) R3is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl; for example,(S) R3is 4- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 4- to 10-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;(T) R3is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;(U) R3is selected from 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, and 8-membered monocyclic heterocyclyl, each optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 5- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;(V) R3is 5-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 2 Rbl, wherein the 5-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from O, S, N, and NRdl; such as(W) R3is tetrahydrofuranyl.

[0049] In addition to embodiments (1) through (4) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:Attorney Ref. No. 01234-0009-00PCT(5) (A) L1is a covalent bond;(B) L1is -(C(Ra2)2)P-;(C) L1is -O-;(D) L1is -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1; (E) L1is -(C(Ra2)2)P-N(Rd2)C*(=O)-, wherein * denotes the point of attachment of L1to X1;(F) L1is -(C(Ra2)2)P-C(=O)N*(Rd2)-, wherein * denotes the point of attachment of L1to X1.

[0050] In addition to embodiments (1) through (5) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(6) (A) X1is Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2; for example, (B) X1is Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2;(C) X1is Cs-Cscycloalkyl optionally substituted with 1 to 4 Rb2;(D) X1is C3-C8cycloalkyl optionally substituted with 1 to 3 Rb2;(E) X1is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted with 1 to 2 Rb2;(F) X1is monocyclic C4cycloalkyl optionally substituted with 1 Rb2;(G) X1is cyclobutyl;(H) X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3; for example,(I) X1is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;(J) X1is 4- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 4- to 10-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;(K) X1is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;(L) X1is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;Attorney Ref. No. 01234-0009-00PCT(M) X1is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;(N) X1is selected from 4-membered monocyclic heterocyclyl, 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, and 8-membered monocyclic heterocyclyl, each optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 5- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;(O) X1is selected from azetidinyl, piperidinyl, and piperazinyl;(P) X1is selected from 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, and 8-membered monocyclic heterocyclyl, each optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 5- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;(Q) X1is 6-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 2 Rb2, wherein the 6-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from O, S, N, and NRd3; such as(R) X1is piperidinyl or piperazinyl.

[0051] In addition to embodiments (1) through (6) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which: (7) (A) L2is a covalent bond;(B) L2is -(C(Ra3)2)P-;(C) L2is -O-;(D) L2is -C(=O)-.

[0052] In addition to embodiments (1) through (7) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(8) (A) X2is a covalent bond;(B) X2is Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb3; for example, (C) X2is Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3;(D) X2is Cs-Cscycloalkyl optionally substituted with 1 to 4 Rb3;(E) X2is C3-C8cycloalkyl optionally substituted with 1 to 3 Rb3;(F) X2is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, each optionally substituted with 1 to 4 Rb3;(G) X2is monocyclic C4cycloalkyl optionally substituted with 1 to 4 Rb3;Attorney Ref. No. 01234-0009-00PCT(H) X2is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4; for example,(I) X2is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;(J) X2is 4- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 4- to 10-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4;(K) X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;(L) X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;(M) X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;(N) X2is selected from 5-membered monocyclic heterocyclyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, and 8-membered monocyclic heterocyclyl, each optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 5- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;(O) X2is selected from 4-membered monocyclic heterocyclyl, 5-membered monocyclic heterocyclyl, and 6-membered monocyclic heterocyclyl, each optionally substituted on a ring carbon with 1 to 2 Rb3, wherein the 4- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms each independently selected from O, S, N, and NRd4; such as (P) X2is azetidinyl, piperidinyl, or piperazinyl.

[0053] In addition to embodiments (1) through (8) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(9) (A) L3is a covalent bond;(B) L3is -(C(Ra4)2)P-;(C) L3is -O-;Attorney Ref. No. 01234-0009-00PCT(D) L3is -C2-C4alkynyl-, provided that X2is a covalent bond or X1- L2- X2form a 5- to 12-membered spiroheterocyclyl or a 6- to 12-membered fused heterocyclyl;(E) L3is -*O-(C(Rel)2)q-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond;(F) L3is -*N(Rd5)-(C(Rel)2)q-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond.

[0054] In addition to embodiments (1) through (9) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(10) (A) Ring B is selected from:Oand <R)n<R(xiii); for example, (B) Ring B is selected from:(viii),Attorney Ref. No. 01234-0009-00PCTwherein “ * ” indicates the point of attachment to (Y1^:(C) Ring B is selected from:wherein “ * ” indicates the point of attachment to (Y^m.

[0055] In addition to embodiments (1) through (10) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(11) (A) YUs NR®;(B) Y1is -*N(Rd9)-C(=O)-, wherein * denotes the point of attachment of Y1to W.

[0056] In addition to embodiments (1) through (11) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(12) (A) R4is H;(B) R4is D;(C) R4is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.

[0057] In addition to embodiments (1) through (12) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(13) (A) Y2is C(Rf2)2;(B) Y2is C(=O).

[0058] In addition to embodiments (1) through (13) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(14) (A) W is CH;Attorney Ref. No. 01234-0009-00PCT(B) W is N.

[0059] In addition to embodiments (1) through (14) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(15) (A) Ralis H;(B) Ralis D;(C) Ralis halo;(D) Ralis OH;(E) Ralis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) Ralis selected from Cialkoxy, C2alkoxy, Csalkoxy, and C4alkoxy;(G) Ralis a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;(H) Ralare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy.

[0060] In addition to embodiments (1) through (15) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(16) (A) Ra2is H;(B) Ra2is D;(C) Ra2is halo;(D) Ra2is OH;(E) Ra2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) Ra2is selected from Cialkoxy, C2alkoxy, Csalkoxy, and C4alkoxy;(G) Ra2is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] In addition to embodiments (1) through (16) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(17) (A) Ra3is H;(B) Ra3is D;(C) Ra3is halo;(D) Ra3is OH;(E) Ra3is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) Ra3is selected from Cialkoxy, C2alkoxy, Csalkoxy, and C4alkoxy;(G) Ra3is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0062] In addition to embodiments (1) through (17) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:Attorney Ref. No. 01234-0009-00PCT(18) (A) Ra4is H;(B) Ra4is D;(C) Ra4is halo;(D) Ra4is OH;(E) Ra4is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) Ra4is selected from Cialkoxy, C2alkoxy, Csalkoxy, and C4alkoxy;(G) Ra4is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0063] In addition to embodiments (1) through (18) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(19) (A) Rblis D;(B) Rblis halo;(C) Rblis OH;(D) Rblis CN;(E) Rblis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) Rblis selected from Cialkoxy, C2alkoxy, Csalkoxy, and C4alkoxy;(G) Rblis a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;(H) two Rblattached to the same atom, form a =0;(I) Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci- Csalkoxy.

[0064] In addition to embodiments (1) through (19) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(20) (A) Rb2is D;(B) Rb2is halo;(C) Rb2is OH;(D) Rb2is CN;(E) Rb2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rb2attached to the same atom, form a =0.

[0065] In addition to embodiments (1) through (20) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(21) (A) Rb3is D;(B) Rb3is halo;(C) Rb3is OH;Attorney Ref. No. 01234-0009-00PCT(D) Rb3is CN;(E) Rb3is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rb3attached to the same atom, form a =0.

[0066] In addition to embodiments (1) through (21) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(22) (A) Rb4is D;(B) Rb4is halo;(C) Rb4is OH;(D) Rb4is CN;(E) Rb4is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rb4attached to the same atom, form a =0.

[0067] In addition to embodiments (1) through (22) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(23) (A) Rb5is D;(B) Rb5is halo;(C) Rb5is OH;(D) Rb5is CN;(E) Rb5is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(F) two Rb5attached to the same atom, form a =0.

[0068] In addition to embodiments (1) through (23) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(24) (A) RC1is D;(B) Rclis halo;(C) RC1is OH;(D) RC1is CN;(E) Rclis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.

[0069] In addition to embodiments (1) through (24) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(25) (A) Rc2is D;(B) Rc2is halo;(C) Rc2is OH;(D) Rc2is CN;(E) Rc2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.Attorney Ref. No. 01234-0009-00PCT

[0070] In addition to embodiments (1) through (25) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(26) (A) Rc3is H;(B) Rc3is D;(C) Rc3is halo;(D) Rc3is OH;(E) Rc3is CN;(F) Rc3is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.

[0071] In addition to embodiments (1) through (26) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(27) (A) Rdlis H;(B) Rdlis D;(C) Rdlis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rdlis a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0072] In addition to embodiments (1) through (27) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(28) (A) Rd2is H;(B) Rd2is D;(C) Rd2is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd2is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0073] In addition to embodiments (1) through (28) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(29) (A) Rd3is H;(B) Rd3is D;(C) Rd3is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd3is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0074] In addition to embodiments (1) through (29) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(30) (A) Rd4is H;(B) Rd4is D;(C) Rd4is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;Attorney Ref. No. 01234-0009-00PCT(D) Rd4is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0075] In addition to embodiments (1) through (30) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(31) (A) Rd5is H;(B) Rd5is D;(C) Rd5is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd5is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0076] In addition to embodiments (1) through (31) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(32) (A) Rd6is H;(B) Rd6is D;(C) Rd6is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd6is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0077] In addition to embodiments (1) through (32) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(33) (A) Rd7is H;(B) Rd7is D;(C) Rd7is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd7is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] In addition to embodiments (1) through (33) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(34) (A) Rd8is H;(B) Rd8is D;(C) Rd8is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd8is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0079] In addition to embodiments (1) through (34) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(35) (A) Rd9is H;(B) Rd9is D;Attorney Ref. No. 01234-0009-00PCT(C) Rd9is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rd9is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0080] In addition to embodiments (1) through (35) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(36) (A) Rdl° is H;(B) Rdl° is D;(C) Rdl° is selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(D) Rdl° is a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0081] In addition to embodiments (1) through (36) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(37) (A) Relis D;(B) Relis halo;(C) Relis OH;(D) Relis CN;(E) Relis N(Rdl0)2;(F) Relis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(G) Relis selected from Cialkoxy, C2alkoxy, Csalkoxy, and C4alkoxy.

[0082] In addition to embodiments (1) through (37) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(38) (A) Rflis H;(B) Rflis D;(C) Rflis halo;(D) Rflis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl;(E) two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0083] In addition to embodiments (1) through (38) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(39) (A) RGis H;(B) RGis D;(C) RGis halo;(D) RGis selected from Cialkyl, C2alkyl, Csalkyl, and C4alkyl.Attorney Ref. No. 01234-0009-00PCT

[0084] In addition to embodiments (1) through (39) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(40) (A) m is 0;(B) m is 1.

[0085] In addition to embodiments (1) through (40) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(41) (A) n is 0;(B) n is 1;(C) n is 2;(D) n is 3;(E) n is 4.

[0086] In addition to embodiments (1) through (41) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(42) (A) p is 0;(B) p is 1;(C) p is 2.

[0087] In addition to embodiments (1) through (42) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(43) (A) q is 0;(B) q is 1;(C) q is 2.

[0088] In addition to embodiments (1) through (43) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(44) (A) t is 0;(B) tis l;(C) t is 2.

[0089] In addition to embodiments (1) through (44) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(45) (A) the compound is represented by Formula (III):H N NY1 / m,c2.Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (IV):or a pharmaceutically acceptable salt thereof;(C) the compound is represented by Formula (V):Oor a pharmaceutically acceptable salt thereof;(D) the compound is represented by Formula (VI):or a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (VII):or a pharmaceutically acceptable salt thereof;(F) the compound is represented by Formula (VIII):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(G) the compound is represented by Formula (IX):or a pharmaceutically acceptable salt thereof;(H) the compound is represented by Formula (X):or a pharmaceutically acceptable salt thereof;(I) the compound is represented by Formula (XI):R3R1—or a pharmaceutically acceptable salt thereof;(J) the compound is represented by Formula (XII):or a pharmaceutically acceptable salt thereof;Attorney Ref. No. 01234-0009-00PCT(K) the compound is represented by Formula (XIII):or a pharmaceutically acceptable salt thereof;(L) the compound is represented by Formula (XIV):or a pharmaceutically acceptable salt thereof;(M) the compound is represented by Formula (XV):or a pharmaceutically acceptable salt thereof.

[0090] In addition to embodiments (1) through (45) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(46) (A) the compound is represented by Formula (II):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 4 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;Attorney Ref. No. 01234-0009-00PCTL1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, -(C(Ra2)2)P-C*(=O)-, -(C(Ra2)2)P- N(Rd2)C*(=O)-, and -(C(Ra2)2)P-C(=O)N*(Rd2)- wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is selected from a covalent bond, -(C(Ra3)2)P-, -O-, and -C(=O)-;X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb3, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd6;Ring B is selected from:Oand (Rc2)n(Rc3)t(xiii);Attorney Ref. No. 01234-0009-00PCTY1is selected from NRd9and -*N(Rd9)-C(=O)-, wherein * denotes the point of attachment of Y1to W;R4is selected from H, D, and Ci-C4alkyl;Y2is C(Re)2 or C(=O);W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic C3-C6 cycloalkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic Cs-Cecycloalkyl, or two Rblattached to the same atom, form a =0;Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, CN, and Ci-C4alkyl, or two Rb2, Rb3, or Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, OH, CN, and Ci-C4alkyl;Rc3are each independently selected from H, D, halo, OH, CN, and Ci-C4alkyl;Rdl, Rd2, Rd3, Rd4, Rd6, Rd8, and Rd9are each independently selected from H, D, Ci-C4alkyl, and monocyclic Cs-Cecycloalkyl;Rfland Rf2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; m is 0 or 1;n is 0, 1, 2, 3, or 4;p is 0, 1, or 2;q is 0, 1, or 2; andtis 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0091] In addition to embodiments (1) through (46) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(47) (A) the compound is represented by Formula (Ila):R3H0N N1 N 1 / R1-N y^ Z^LLi_xi_L2-X2-L B J ° ll^R2 (R )n(Ila), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;Attorney Ref. No. 01234-0009-00PCTR3is selected from Ci-Cealkyl optionally substituted with 1 to 4 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, and -(C(Ra2)2)P-C*(=O)- wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd6;Ring B is selected from:Y2is C(Re)2 or C(=O); W is CH or N;Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic Cs-Cecycloalkyl, or two Rblattached to the same atom, form a =0;Rb2, Rb3, and Rb4are each independently selected from H, D, halo, OH, CN, and Ci-C4alkyl, or two Rb2, Rb3, or Rb4attached to the same atom, form a =0;Rc1and Rc2are each independently selected from D, halo, OH, CN, and C1-C4alkyl;Rdl, Rd3, Rd4, Rd6, and Rd8are each independently selected from H, D, and Ci-C4alkyl;Attorney Ref. No. 01234-0009-00PCTRfland Rf2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; n is 0, 1, 2, 3, or 4; andp is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0092] In addition to embodiments (1) through (47) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(48) no more than three of L1, L2, X2, and L3are simultaneously a covalent bond.

[0093] In addition to embodiments (1) through (48) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(49) (A) X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;(B) X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;(C)lA(D)Attorney Ref. No. 01234-0009-00PCTwherein “ * ” indicates the point of attachment to L3- Ring B;(E) X1-L2-X2is:wherein “ * ” indicates the point of attachment to L3- Ring B;(G) L1- X^L2- X2-L3is:Attorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTwherein “ * ” indicates the point of attachment to Ring B; for example,(H) L1- X1-L2- X2-L3is:Attorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTwherein “ * ” indicates the point of attachment to Ring B;(J) L1- X1- L2- X2- L3is:Attorney Ref. No. 01234-0009-00PCTwherein “ * ” indicates the point of attachment to Ring B;(K) X2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd7;(L) X2-L3is:Attorney Ref. No. 01234-0009-00PCT(M) X2-L3is:wherein “ * ” indicates the point of attachment to Ring B.

[0094] In addition to embodiments (1) through (49) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(50) (A) the compound is represented by Formula (IIIa), (IIIb), (IIIc), (IIId), or (IIIe):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (IVa), (IVb), (IVc), (IVd), (IVe), (IVf), (IVg), or (IVh):(RC2)" (IVC),Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(C) the compound is represented by Formula (Va), (Vb), (Vc), (Vd), (Ve), or (Vf):OAttorney Ref. No. 01234-0009-00PCT(Vc),or a pharmaceutically acceptable salt thereof;Attorney Ref. No. 01234-0009-00PCT(D) the compound is represented by Formula (Via), (VIb), (Vic), (Vid), (Vie), (VIf), or (VIg):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(E) the compound is represented by Formula (Vila), (Vllb), (Vile), (Vlld), or (Vile):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(F) the compound is represented by Formula (Villa), (Vlllb), (VIIIc), (Vllld), or (Ville):(Villa),Attorney Ref. No. 01234-0009-00PCT oor a pharmaceutically acceptable salt thereof;(G) the compound is represented by Formula (IXa), (IXb), (IXc), or (IXd):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(H) the compound is represented by Formula (Xa), (Xb), (Xc), or (Xd):Attorney Ref. No. 01234-0009-00PCT(Xd), or a pharmaceutically acceptable salt thereof;(I) the compound is represented by Formula (Xia), (Xlb), (XIc), or (Xld):(Xia),or a pharmaceutically acceptable salt thereof;(J) the compound is represented by Formula (Xlla), (Xllb), (XIIc), or (Xlld):Attorney Ref. No. 01234-0009-00PCT(Xlla),(Xlld), or a pharmaceutically acceptable salt thereof;(K) the compound is represented by Formula (Xllla), (Xlllb), (XIIIc), or (Xllld):Attorney Ref. No. 01234-0009-00PCT(XIIIc),R4(Xllld),or a pharmaceutically acceptable salt thereof;(L) the compound is represented by Formula (XlVa), (XlVb), (XIVc), or (XlVd):(XlVa),(XIVc),Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof;(M) the compound is represented by Formula (XVa), (XVb), (XVc), or (XVd):R4(XVc),(XVd), or a pharmaceutically acceptable salt thereof.Attorney Ref. No. 01234-0009-00PCT

[0095] In addition to embodiments (1) through (50) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(51) (A) the compound is represented by Formula (Illa):R3or a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (Illd):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -(C(Ra2)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb4are each independently selected from D, halo, OH, and CN;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdland Rd6are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:Attorney Ref. No. 01234-0009-00PCT(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,(C) the compound is represented by Formula (Hid):l-lor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Cs-Cgcycloalkyl optionally substituted with 1 to 3 Rbl;L1is -(C(Ra2)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ra2are each independently selected from H, D, and Ci-Csalkyl;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rd6is selected from H, D, and Ci-Csalkyl;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (D) the compound is represented by Formula (Hid):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Cs-Cgcycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond or -(C(Ra2)2)P-;Attorney Ref. No. 01234-0009-00PCTX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ra2are each independently H or Ci-Csalkyl;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently halo or OH;Rcland Rc2are each independently halo or OH;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0096] In addition to embodiments (1) through (51) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(52) (A) the compound is represented by Formula (IVb):or a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (IVg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, whereinAttorney Ref. No. 01234-0009-00PCTthe 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb2and Rb3are each independently selected from D, halo, OH, and CN;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,(C) the compound is represented by Formula (IVg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is -(C(Ra2)2)P-;X1is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond;X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Attorney Ref. No. 01234-0009-00PCTRa2are each independently selected from H, D, and Ci-Csalkyl;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rd3and Rd4are each independently selected from H, D, and Ci-Csalkyl;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (D) the compound is represented by Formula (IVg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond or -(C(Ra2)2)P-;X1is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;L2is a covalent bond;X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ra2are each independently H or Ci-Csalkyl;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently halo or OH;Rcland Rc2are each independently halo or OH;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (E) the compound is represented by Formula (IVc):Attorney Ref. No. 01234-0009-00PCT(IVc), or a pharmaceutically acceptable salt thereof;(F) the compound is represented by Formula (IVh):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -(C(Ra2)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb4are each independently selected from D, halo, OH, and CN;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdland Rd6are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:Attorney Ref. No. 01234-0009-00PCT(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,(G) the compound is represented by Formula (IVh):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rd6is selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (H) the compound is represented by Formula (IVh):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Ci-C4alkyl optionally substituted with 1 to 3 Ralor Cs-Cgcycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond;Attorney Ref. No. 01234-0009-00PCTX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ralare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently halo or OH;Rcland Rc2are each independently halo or OH; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0097] In addition to embodiments (1) through (52) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(53) (A) the compound is represented by Formula (Vb):or a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (Ve):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted onAttorney Ref. No. 01234-0009-00PCTa ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, and CN, or two Rb2, Rb3, or Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdl, Rd3, Rd4, Rd6, and Rd8are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,(C) the compound is represented by Formula (Ve):Attorney Ref. No. 01234-0009-00PCToor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cgcycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -O-;X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 10- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, Rd4, and Rd8are each independently selected from H, D, and Ci-Csalkyl;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (D) the compound is represented by Formula (Ve):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cgcycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd6, and Rd8are each independently selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (E) the compound is represented by Formula (Vf):OAttorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, and -O-;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, and CN, or two Rb2, Rb3, or Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdl, Rd3, Rd4, and Rd6are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,Attorney Ref. No. 01234-0009-00PCT(F) the compound is represented by Formula (Vf):Oor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -O-;X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 10- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (G) the compound is represented by Formula (Vf):Attorney Ref. No. 01234-0009-00PCToor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond;X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond;X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;(H) the compound is represented by Formula (Vf):Attorney Ref. No. 01234-0009-00PCToor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;L1is a covalent bond;X1is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;L2is a covalent bond;X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ralare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently halo or OH;Rcland Rc2are each independently halo or OH; andn is 0, 1, or 2;(I) the compound is represented by Formula (Vf):Oor a pharmaceutically acceptable salt thereof, whereinAttorney Ref. No. 01234-0009-00PCTR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, and OH;Rdland Rd6are selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (J) the compound is represented by Formula (Vf):Oor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Raland Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond;Attorney Ref. No. 01234-0009-00PCTX1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, and OH;Rd6is selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (K) the compound is represented by Formula (Vf):Oor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 6-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 6-membered heterocyclyl has 1 or 2 ring heteroatoms each independently selected from O and N;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ralare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently halo or OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently halo or OH; andAttorney Ref. No. 01234-0009-00PCTn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0098] In addition to embodiments (1) through (53) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(54) (A) the compound is represented by Formula (VIb):NRf1>fior a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (Vie):R3H N N>fi >fi(Vie), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, and -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;Attorney Ref. No. 01234-0009-00PCTL2is a covalent bond or -(C(Ra3)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, and CN;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdl, Rd3, Rd4, and Rd6are each independently selected from H, D, and Ci-C4alkyl;Rflare each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic C Cecycloalkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present;for example,(C) the compound is represented by Formula (Vie):R3H N N>fi >fi(Vie), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;Attorney Ref. No. 01234-0009-00PCTR3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -O-;X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 10- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl;Rflare each independently selected from H, D, halo, and Ci-Csalkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic C Cecycloalkyl;n is 0, 1, or 2; andp is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (D) the compound is represented by Formula (Vie):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;Attorney Ref. No. 01234-0009-00PCTR3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, and -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdland Rd6are each independently selected from H, D, and Ci-Csalkyl;Rflare each independently selected from H, D, halo, and Ci-Csalkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic C Cecycloalkyl;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (E) the compound is represented by Formula (VIf) or Formula (VIg):(VIf), or(VIg),Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, and -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4; orX1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, and CN;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdl, Rd3, Rd4, and Rd6are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present;for example,(F) the compound is represented by Formula (VIf) or Formula (VIg):Attorney Ref. No. 01234-0009-00PCTooor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -O-;X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 10- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond or -(C(Ra3)2)P-;X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Ra3are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl;Attorney Ref. No. 01234-0009-00PCTn is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (G) the compound is represented by Formula (VIf) or Formula (VIg):R3H N N(VIf), orR3H N N(VIg), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond;X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond;X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Attorney Ref. No. 01234-0009-00PCTRblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (H) the compound is represented by Formula (VIf) or Formula (VIg):R3H N N(VIf), orR3H N N(VIg), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond;X1is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;L2is a covalent bond;Attorney Ref. No. 01234-0009-00PCTX2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (I) the compound is represented by Formula (VIf) or Formula (VIg):OOor a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;L1is a covalent bond;Attorney Ref. No. 01234-0009-00PCTX1is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;L2is a covalent bond;X2is 3- to 8-membered monocyclic heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 8-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ralare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb2and Rb3are each independently halo or OH;Rcland Rc2are each independently halo or OH; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present;(J) the compound is represented by Formula (VIf) or Formula (VIg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted onAttorney Ref. No. 01234-0009-00PCTa ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, and OH;Rdland Rd6are each independently selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (K) the compound is represented by Formula (VIf) or Formula (VIg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is selected from a covalent bond, -(C(Ra2)2)P-, and -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;Attorney Ref. No. 01234-0009-00PCTX1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rd6are each independently selected from H, D, and Ci-Csalkyl;n is 0, 1, or 2; andP is 1;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (L) the compound is represented by Formula (VIf) or Formula (VIg):or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Raland Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Attorney Ref. No. 01234-0009-00PCTRalare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rblare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently halo or OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently halo or OH; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

[0099] In addition to embodiments (1) through (54) in the preceding paragraphs, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, include those in which:(55) (A) the compound is represented by Formula (VHb):N, C1(VHb),or a pharmaceutically acceptable salt thereof;(B) the compound is represented by Formula (Vile):R3N, C1(Vile), or a pharmaceutically acceptable salt thereof, whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -(C(Ra2)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on aAttorney Ref. No. 01234-0009-00PCTring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb4are each independently selected from D, halo, OH, and CN, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently selected from D, halo, OH, and CN;Rdl, Rd6, and Rd8are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,(C) the compound is represented by Formula (Vile):or a pharmaceutically acceptable salt thereof; whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is Ci-C4alkyl optionally substituted with 1 to 3 Ral;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rd6and Rd8are each independently selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2;Attorney Ref. No. 01234-0009-00PCT(D) the compound is represented by Formula (Vllf):or a pharmaceutically acceptable salt thereof; whereinR1and R2are each independently selected from H, D, and Ci-C4alkyl;R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;L1is a covalent bond or -(C(Ra2)2)P-;X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;Ra2are each independently selected from H, D, and Ci-C4alkyl;Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;Rb4are each independently selected from D, halo, OH, and CN;Rcland Rc2are each independently selected from D, halo, and OH;Rdland Rd6are each independently selected from H, D, and Ci-C4alkyl;n is 0, 1, 2, or 3; andp is 1 or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; for example,(E) the compound is represented by Formula (Vllf):Attorney Ref. No. 01234-0009-00PCTor a pharmaceutically acceptable salt thereof; whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected selected from Ci-C4alkyl optionally substituted with 1 to 3 Raland C3- Cscycloalkyl optionally substituted with 1 to 3 Rbl;L1is a covalent bond;X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, and N;Ralare each independently selected from halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently halo or OH, or two Rb4attached to the same atom, form a =0;Rcland Rc2are each independently halo or OH; andn is 0, 1, or 2;provided that:(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present; (F) the compound is represented by Formula (Vllf):or a pharmaceutically acceptable salt thereof; whereinR1and R2are each independently selected from H, D, and Ci-Csalkyl;R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral;L1is a covalent bond;Attorney Ref. No. 01234-0009-00PCTX1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;Rb4are each independently selected from D, halo, and OH;Rcland Rc2are each independently selected from D, halo, and OH;Rd6is selected from H, D, and Ci-Csalkyl; andn is 0, 1, or 2.

[0100] In some embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.Table 1. Selected bifunctional degrader compounds.Ex. Cmpd. StructureNo. No.5 1 N N N J \i_ZI / Z^-HXO48 215 3N N hkI J XJ\JQNHN— <OrAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCT Ex. Cmpd. StructureNo. No.16 81 ^..oz,0 / Jk N / o=\ / r YNY y zH 0 YY7 9 IZN N N rj \_ I J 1 JGM0 Y'N-YYNY^XOY-N7Y^oN / OA NY / Y NHXO \Y47 10 0F-O-N^VN7\I— f~ VNH\— / v \ _ / \NN Y\ °YYYY N7 / ^N / |OY T ftX=\Y\ Y TFAu\ ZI NYno nH° 6 o8 11H N N N J o0r..c co vJ / Y / Y\Y\- N X N.oYN / li NY. H 1Hxo YY9 12H vN N N |4 o,., C V J VJ / Attorney Ref. No. 01234-0009-00PCTEx. Cmpd. StructureNo. No.49 13H O N O1 T CC N N N \ iqJ o W W 'Co v H OR O N O1 T N-V N N N Kj o j j w y 10 14PX NPA?“ <~PA H O ° A".ORMV 2 A, nL NN^=z\°H cP G ^P AWE45 15A dJAHi0Mr « CM yy C Y 1 V r<" A < AW0Attorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCT Ex. Cmpd. StructureNo. No.13 19HF'" Pyy\\ ° ° / o o O pXJ XXH_ / \ IZ L3\3 < IZ TZZZ^>z z14 20 O oZZ Z N Z V'^^S=C (yryy H y N N N jq O.-z zo DCJJ U M _ W■ / \" N X z z N ".O=\ / Ti 'NH o1 21 o o Z ZZ^Z^ xiiZb Jbz zZIZTz zpp1 CL £o olX v yp L L ^ JXIZ'H"> N'‘ yyy y o o / / 3 22Attorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTEx. Cmpd. StructureNo. No.52 31r j OR u O^N^oocNkn rn-k ■Ho NAOW19 33H V" N N N id orNU wN-NZrZ\ j / ry\ N Jo^\ / r 7N H^L O L U37 34 o N H \20 35H ) — N N N J orJJ'KN / Z57 36C^ " Z,n-y y°^NAOR / ZHuVJ 58 37JuO7~ °^NAOF' / (HuAttorney Ref. No. 01234-0009-00PCT Ex. Cmpd. StructureNo. No.59 381 ^ZD J o o < A HNAOu F~A \ —1z64 39 O ^ zVAo / A. \._ / \ / x / \ _ ( / / — \ \— \ / VN VH N / >OA A Z S ”°AhA a°-X=<A nA 60 4081zbTZQ^f ZIA Z\ °38 41A\ °ZA 2 / ^~NHA / / u1O ^Xz-\ / o °^NAOJ O Z I 1 A21 4243 430 H TA'^AO^AXJ XAA 22 44Attorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCT Ex. Cmpd. StructureNo. No.26 53HyrN N N id o. V27 54J / / O °^NAOo28 55 p O N HHNy F v \^N z yy.,,o\ Ay p <: A-z<xQ - y z° ° ORy N O^° HNM / _ / T y y. \. A N29 56H Z° ° NNy yM / _ £ V ^NO^ \° \ p O N H y,lO30 57y y y --y 6 31 58Attorney Ref. No. 01234-0009-00PCT Ex. Cmpd. StructureNo. No.40 59 OMe H N N N id o O u.1AZ\ / O / c> < Nw / ° o7 V HOzA IZ A A M' ■ ’ / IZJ A\ O32 60,° Qp ° M ^Nx N \ / °“ HN-K KM / FN / t)\zV ^NZ7oM )- j —z X X x M_o> r 7 ccII o II33 61z~~VU^ X3 \ OuL4 62 P ^3°K / °AI \ z J1ZTo o o o X / v \ \ / / K / o 35 6336a 64aAttorney Ref. No. 01234-0009-00PCTEx. Cmpd. StructureNo. No.36b 64b# hf Y N— ( / NHXA 0 OR ' 'A'X H0. —.. —. "" V y— N X N-# V- NH° u-^>i6 fHz\ 77 65H ) — N N id oO ° / 7\^ZHN— < / O=Z / N I T83 66N N N K] orNXI XXM -N=< / z / K N JHo U92 67 HCL N ^.0 \ V" v H L XNN o x i H I XX Zr \ xOR H O N O I T 0 y^N-x / n Z i T T / W cy X^ / Attorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCT Ex. Cmpd. StructureNo. No.72 73 OH H \ / J N N N O, a. y-N | |90 74 H N N N 00X¥ ¥DV-N7J D^y. •ft ¥99 75...x A ik65 7687 77 OHH ¥ ^YNYNV\ ° nrAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTAttorney Ref. No. 01234-0009-00PCTCompound Synthesis

[0101] The compounds described herein can be made using known organic syntheses and commercially available starting materials, or the methods provided herein. By way of example and not limitation, compounds of Formula (I) or intermediates for synthesizing compounds of Formula (I) can be prepared as outlined in Scheme(s) 1-7, as well as in the Examples set forth herein. It should be noted that one skilled in the art would know how to modify the procedures set forth in the illustrative schemes and Examples to arrive at the desired products. This includes the use of protecting groups: in some cases certain substituents may interfere with the chemistry in these schemes, in which case appropriate protecting groups can be employed to avoid unwanted reactivity and side products.Attorney Ref. No. 01234-0009-00PCTScheme 1

[0102] LG is a suitable leaving group, typically halo and preferably Br

[0103] PG = H, or a suitable protecting group, typically PMB (p-methoxybenzyl)

[0104] According to a first process, compounds of Formula (I), may be prepared from the compounds of Formula (IF) and (III’) using a palladium catalysed, cross-coupling reaction. Typical cross-coupling conditions comprise reaction of the amine compound of Formula (IF) with a compound of Formula (IIP), a palladium catalyst in the presence of an inorganic base, in a suitable solvent at between rt and the reflux temperature of the reaction. Preferred conditions comprise, reaction of compounds of Formula (IF) and (IFF), in the presence of Pd-PEPPSI-IFFeptCl, RuPhos Pd G3, RuPhos Pd G2 with RuPhos, or Brettphos Pd G4 and a suitable base such as Cs2CO3 in a suitable solvent such as dioxane or toluene at between rt and 100 °C. If a suitable protecting group (PG = PMB) is present in a compound of Formula (IFF) a 2-step method involving the above described Pd catalysed cross-coupling followed by deprotection using trifluoromethane-sulfonic acid and TFA at rt to 40 °C is used to give compounds of Formula (I).(I)Scheme 2

[0105] PG = H, or a suitable protecting group, typically PMB (p-methoxybenzyl)

[0106] According to a second process, compounds of Formula (I), may be prepared from the compounds of Formula (IV’) and (V’) using a reductive amination process. Typical conditions comprise reaction of the amine compound of Formula (V’) with a carbonyl compound of Formula (IV’) in a suitable aprotic solvent, organic base in the presence of a suitable organic acid at a suitable temperature of between rt and reflux in the presence of an appropriate reducing agent. Preferred conditions comprise, reaction of compounds of Formula (IV’) and (V’), in the presence of TEA and acetic acid in DMSO at rt followed by the addition of STAB at rt. If aAttorney Ref. No. 01234-0009-00PCTsuitable protecting group (PG = PMB) is present in a compound of Formula (V’) a 2-step method involving the above described reductive amination followed by deprotection using trifluoromethanesulfonic acid and TFA at rt to 40 °C is used to give compounds of Formula (I).Scheme 3

[0107] LG is a suitable leaving group, typically halo and preferably Br

[0108] PG = H, or a suitable protecting group, typically PMB (p-methoxybenzyl)

[0109] According to a third process, compounds of Formula (I), may be prepared from the compounds of Formula (VI’) and (VII’) using a palladium catalysed, cross-coupling reaction. Typical cross-coupling conditions comprise reaction of the amine compound of Formula (VIF) with a compound of Formula (VI’), a palladium catalyst in the presence of an inorganic base, in a suitable solvent at between rt and the reflux temperature of the reaction. Preferred conditions comprise, reaction of compounds of Formula (VI’) and (VII’), in the presence of Brettphos Pd G4 and a suitable base such as KOAc or cesium carbonate in a suitable solvent such as dioxane and / or DMA at between rt and 100 °C. If a suitable protecting group (PG = PMB) is present in a compound of Formula (VII’) a 2-step method involving the above described Pd catalysed crosscoupling followed by deprotection using trifluoromethanesulfonic acid and TFA at rt to 40 °C is used to give compounds of Formula (I).Attorney Ref. No. 01234-0009-00PCTR3(VI')Scheme 4

[0110] According to a fourth process, compounds of Formula (VI’) may be prepared from the compounds of Formula (VIII’), (IX’), (X’), (XI’) and (XIF) using a 3-step method as shown in Scheme 4. Typical conditions for Step 1 comprise the reaction of a compound of Formula (VIIF) and a primary amine of Formula (IX’) in the presence of a suitable base in an aprotic solvent at a suitable temperature between rt and 100 °C. Preferred conditions comprise, reaction of compounds of Formula (VIIF) and (IX’), in the presence of DIPEA in MeCN at 60 °C.Typical conditions for Step 2 comprise palladium mediated cross-coupling reaction of a compound of Formula (X’) and an amide of Formula (XI’) in the presence of a suitable catalyst, a base and Cui in an aprotic solvent at a suitable temperature between rt and 100 °C. Preferred conditions comprise, reaction of compounds of Formula (X’) and (XF), in the presence of Pd(PPh3)2Ch, DIPEA and DIPEA in DMF at 80 °C. Typical conditions for Step 3 comprise a base mediated cyclisation reaction of a compound of Formula (XIF) a base in an aprotic solvent at a suitable temperature between rt and 100 °C. Preferred conditions comprise, cyclisation of a compound of Formula (XII’) in the presence of cesium carbonate in DMSO at 30 °C.

[0111] It will be appreciated by those skilled in the art that it may be necessary to utilize a suitable protecting group strategy for the preparation of compounds of Formula (I). Typical protecting groups may comprise, a carbamate, preferably a Boc or CBz group for the protection of primary or secondary aliphatic amines and p-methoxybenzyl for the protection ofdioxopiperidines.Attorney Ref. No. 01234-0009-00PCTScheme 5

[0112] According to a fifth process, compounds of Formula (I), may be prepared from the compounds of Formula (XIII’) and (XIV’) using a reductive amination process. Typical conditions comprise reaction of the amine compound of Formula (XIV’) with a carbonyl compound of Formula (XIII’) in a suitable aprotic solvent, organic base in the presence of a suitable organic acid at a suitable temperature of between rt and reflux in the presence of an appropriate reducing agent. Preferred conditions comprise, reaction of compounds of Formula (XIII’) and (XIV’), in the presence of TEA and acetic acid in DMSO followed by the addition ofScheme 6

[0113] According to a sixth process, compounds of Formula (I), wherein L2is CH2, may be prepared from the compounds of Formula (XV’) and (XIV’) using a reductive amination process, as described previously in Scheme 5.Attorney Ref. No. 01234-0009-00PCTScheme 7

[0114] According to a seventh process, compounds of Formula (I), wherein L2is CH2, may be prepared from the compounds of Formula (XVI’) and (XVIF) using a reductive amination process, as described previously in Scheme 5.

[0115] It will be appreciated that it may be necessary and / or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

[0116] Compounds that contain one or more stereocenters may be separated into their separate stereoisomers by typical methods such as chiral SFC or chiral HPLC techniques as indicated in the Examples below.

[0117] The use of stereoisomerically pure forms of the compounds disclosed herein, as well as the use of mixtures of those forms, are encompassed by the embodiments disclosed herein. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound may be used in methods and compositions disclosed herein. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.

[0118] Compounds having one or more chiral centers can exist in various stereoisomeric forms, / .<., each chiral center can have an R or S configuration, or can be a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers having two or more chiral centers that are not identical and are not mirror images of each other.

[0119] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration isAttorney Ref. No. 01234-0009-00PCTindicated in the chemical name by “7?” or “S”) or structure e.g., the configuration is indicated by “wedge” bonds), the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (except when the designation “rac” or “racemate” accompanies the structure or name, as explained in the following two paragraphs).

[0120] When two stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two stereoisomers is intended, but not both.

[0121] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds disclosed herein.

[0122] “Enantiomerical purity” is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

[0123] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that, unless otherwise indicated, one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers are included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.

[0124] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “A”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[0125] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent, asAttorney Ref. No. 01234-0009-00PCTindicated in the Examples below. See also, e.g., Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 332 25 (1977); Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN, 1972); Todd, M., Separation Of Enantiomers: Synthetic Methods (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2014); Toda, F., Enantiomer Separation: Fundamentals and Practical Methods (Springer Science & Business Media, 2007); Subramanian, G. Chiral Separation Techniques: A Practical Approach (John Wiley & Sons, 2008); Ahuja, S., Chiral Separation Methods for Pharmaceutical and Biotechnological Products (John Wiley & Sons, 2011).

[0126] Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0127] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan.

[0128] It should also be noted the compounds disclosed herein can contain unnatural proportions of atomic isotopes at one or more of the atoms. In some embodiments, the compounds may be radiolabeled with radioactive isotopes, such as, for example, tritium (3H), iodine-125 (125I), sulfur-35 (35S), or carbon-14 (14C), or may be isotopically enriched, such as with deuterium (2H), carbon-13 (13C), or nitrogen-15 (15N). As used herein, an “isotopologue” is an isotopically enriched compound. The term “isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term “isotopic composition” refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In someAttorney Ref. No. 01234-0009-00PCTembodiments, there are provided isotopologues of the compounds disclosed herein, for example, the isotopologues are deuterium, carbon-13, and / or nitrogen-15 enriched compounds. As used herein, “deuterated”, means a compound wherein at least one hydrogen (H) has been replaced by deuterium (indicated by D or2H), that is, the compound is enriched in deuterium in at least one position.

[0129] In the compounds of the disclosure, any position specifically designated as “D” or “deuterium” is understood to have deuterium enrichment at least 5, 10, 25, 50, 80, 90, 95, 98 or 99%. “Deuterium enrichment” is a mole percent and is determined by dividing the number of compounds with deuterium at the indicated position by the total number of all of the compounds. When a position is designated as “H” or “hydrogen”, the position has hydrogen at its natural abundance. When a position is silent as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance. One specific alternative embodiment is directed to a compound of the disclosure having deuterium enrichment of at least 5, 10, 25, 50, 80, 90, 95, 98 or 99% at one or more positions not specifically designated as “D” or “deuterium”.

[0130] As used herein, many moi eties (e.g., alkyl, alkoxy, cycloalkyl or heterocyclyl) are referred to as being either “substituted” or “optionally substituted”. When a moiety is modified by one of these terms, unless otherwise noted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted, which includes one or more substituents. Where if more than one substituent is present, then each substituent may be independently selected. Such means for substitution are well-known in the art and / or taught by the instant disclosure. The optional substituents can be any substituents that are suitable to attach to the moiety.Pharmaceutical Compositions and Dosages

[0131] The present disclosure also relates to pharmaceutical compositions comprising compounds or a pharmaceutically acceptable salt of any of the compounds disclosed in this application and at least one pharmaceutically acceptable excipient.

[0132] Non-limiting examples of pharmaceutically acceptable excipients, carriers, and / or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, hydroxymethycellulose, fatty acid esters, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such asAttorney Ref. No. 01234-0009-00PCTlubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and / or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds or pharmaceutically acceptable salts thereof.

[0133] The pharmaceutical compositions of the disclosure optionally include one or more pharmaceutically acceptable excipients, carriers and / or diluents therefor, such as lactose, starch, cellulose and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999. The carriers, diluents and / or excipients are “acceptable” in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0134] The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, such as general the route of administration, the time of administration, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular active ingredient employed, the type and severity of the disease or condition, the rate of excretion of the particular active ingredient being employed, and on the characteristics of the subject, such as the age, sex, body weight, general health and prior medical history of the patient being treated, tolerance to drugs, and like factors well known in the medical arts. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57th ed., 2003).Attorney Ref. No. 01234-0009-00PCT

[0135] In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.Methods of Treatment

[0136] The disclosure provides methods of modulating (e.g., degrading) CDK4 activity and therefore are useful for treating diseases for which CDK4 are dysregulated, such as cancer. In some embodiments, the method of modulating is a method of degrading CDK4 comprising contacting CDK4 with a compound of the disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the method of modulating is a method of degrading CDK4 in a subject in need thereof, comprising contacting CDK4 with an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0137] Described herein is a method of treating a disease, condition, or cancer mediated by CDK4 comprising providing to a subject in need thereof any of the compounds disclosed in this application, or a pharmaceutically acceptable salt thereof.

[0138] In another aspect, provided herein is a method of treating a cancer in a patient in need thereof comprising administering to a patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0139] In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of cancers.

[0140] In another aspect, provided herein is the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for the treatment of cancers.

[0141] Compounds of the disclosure, or pharmaceutically acceptable salts thereof, are CDK4 degraders with warheads that target CDK4 and inhibit its function with high potency and selectivity compared to traditional small-molecule inhibitors. Some of the compounds of the disclosure selectively and catalytically degrade their target protein (e.g., CDK4) over other CDKs and other proteins. The ability to selectively target CDK4 with a compound of the disclosure provides advantages in terms of targeted degradation of CDK4 with little to no off-target activity, and an increased probability of clinical success in comparison with traditional small-molecule inhibitors.Attorney Ref. No. 01234-0009-00PCT

[0142] A CDK4 degrader may show degradation that is at least 2-fold relative to another target protein (e.g., at least 10-fold; at least 15-fold; at least 20-fold; at least 30-fold; at least 40-fold selectivity; at least 50-fold; at least 60-fold; at least 70-fold; at least 80-fold; at least 90-fold; at least 100-fold; at least 125-fold; at least 150-fold; at least 175-fold; or at least 200-fold).

[0143] In some alternatives, a CDK4 degrader exhibits at least 15-fold selectivity over another CDK, e.g., CDK1, CDK2, and CDK6. In some embodiments, the compounds of the disclosure are selective against CDK4 versus CDK2. In some embodiments, compounds show at least 10-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 20-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 30-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 40-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 50-fold selectivity for CDK4 versus CDK2. In some embodiments, compounds show at least 100-fold selectivity for CDK4 versus CDK2. For example, compounds show at least 200-fold selectivity for CDK4 versus CDK2.

[0144] In some embodiments, the compounds of the disclosure are selective against CDK4 versus CDK6. In some embodiments, compounds show at least 10-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 20-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 30-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 40-fold selectivity for CDK4 versus CDK6. In some embodiments, compounds show at least 50-fold selectivity for CDK4 versus CDK6.

[0145] In some embodiments, the compounds of the disclosure are selective against CDK4 versus CDK1. In some embodiments, compounds show at least 10-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 20-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 30-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 40-fold selectivity for CDK4 versus CDK1. In some embodiments, compounds show at least 50-fold selectivity for CDK4 versus CDK1.

[0146] Some compounds of the disclosure have the advantage of oral bioavailability. In some embodiments, a compound of the disclosure catalytically degrades its target protein, which may require a lower dose compared to traditional small molecule inhibitor. For example, many CDK4 / 6 inhibitors, including ribociclib, palbociclib, and abemaciclib, bind the adenosine triphosphate (ATP) cleft, which contains the catalytic residues, and compete with ATP to inhibit activity. In some embodiments, a compound of the disclosure is a bifunctional degrader with aAttorney Ref. No. 01234-0009-00PCTwarhead that binds to the target protein (e.g., CDK4) linked to an E3 ubiquitin ligase-binding moiety that recruit E3 ligases to ubiquitinate the target protein and prompt the target protein to be recognized and subsequently degraded by 26S proteasome. The compounds of the disclosure can be used repeatedly to trigger this targeted protein degradation. In some embodiments, a compound of the disclosure may eliminate certain side effects, for example, drug-drug interactions and off-target effects, such as CDK6 mediated heme toxicity.

[0147] In some embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as first line therapy. In other embodiments, a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is administered as second (or later) line therapy.

[0148] In embodiments of the cancers and the methods provided herein, the cancer is a solid tumor cancer. In embodiments, the solid tumor cancer is a carcinoma or a sarcoma. In embodiments, the solid tumor cancer is an adenocarcinoma, a carcinoma, or a cystadenocarcinoma. In some embodiments, the subject has an advanced and / or relapsed solid tumor.

[0149] In embodiments of the methods provided herein, the cancer is selected from bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer, esophageal cancer, gastric cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), and prostate cancer.

[0150] In some embodiments, the cancer is a refractory cancer, which is also referred to as a treatment-resistant cancer.

[0151] In some embodiments of the cancers and methods disclosed herein, the cancer is breast cancer (BC). In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments, the breast cancer is selected from ductal carcinoma in situ, ER+ breast cancer (estrogen receptor positive breast cancer); ER+ / HER2- breast cancer (estrogen receptor positive, human epidermal growth factor 2 negative breast cancer); HR+ breast cancer (hormone receptor positive breast cancer); HR+ / HER2- breast cancer; HER2- breast cancer; HER2+ breast cancer (human epidermal growth factor 2 positive breast cancer); HER2-low breast cancer; invasive ductal carcinoma (IDC); invasive lobular carcinoma, lobular carcinoma in situ, PR+ / HER2- breast cancer (progesterone receptor positive, human epidermal growth factor 2 negative breast cancer); triple negative breast cancer (TNBC); and tubular breast carcinoma. In some embodiments, the breast cancer is HR+ / HER2- BC. In some embodiments,Attorney Ref. No. 01234-0009-00PCTthe breast cancer is ER+ / HER2- BC. In some embodiments, the breast cancer is PR+ / HER2-BC. In some embodiments, the breast cancer is TNBC.

[0152] In some embodiments, the breast cancer is refractory. In some embodiments, the breast cancer is chemotherapy resistant breast cancer, endocrine resistant breast cancer, radiotherapy resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer demonstrating primary or acquired resistance to CDK4 / CDK6 inhibition.

[0153] In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is resistant to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is abemaciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and / or fulvestrant and a second treatment with abemaciclib and / or fulvestrant.

[0154] In some embodiments of the cancers and methods disclosed herein, the cancer is prostate cancer. In some embodiments, the prostate cancer is advanced or metastatic prostate cancer. In some embodiments, the prostate cancer is selected from androgen receptor positive (AR+) prostate cancer, castration-resistant prostate cancer (CRPC), and metastatic castrationresistant prostate cancer. In some embodiments, the prostate cancer is CRPC.

[0155] In one embodiment, the subject has HR+ / HER- breast cancer (including both ER+ / HER2- BC and PR+ / HER2- BC) that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In one embodiment, the subject has TNBC that has progressed despite one or more lines of therapies. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of therapies. In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).Methods of Administration

[0156] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly, etc.) doses over a period of a few days to months, or even years.Combination TherapiesAttorney Ref. No. 01234-0009-00PCT

[0157] In addition, a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure can be co-administered with other therapeutic agents, e.g., an additional anticancer agent. In some embodiments the one or more compounds of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure will be co-administered with other agents. These terms encompass administration of two or more agents to the subject so that both agents and / or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, compounds described herein and the other agent(s) are admixed in the composition. In some embodiments, the other therapeutic agent(s) or other agent(s) is / are one or more additional anticancer agent(s).

[0158] In some embodiments, the additional anticancer agent is a chemotherapeutic agent including, but not limited to, 5-fluorouracil, abraxane, camptothecin, capecitabine, carboplatin, cisplatin, cyclophosphamide, dacarbazine, docetaxel, doxorubicin, epirubicin, eribulin, etoposide, floxuridine, gemcitabine, ifosfamide, irinotecan, ixabepilone, methotrexate, mitomycin, oxaliplatin, paclitaxel, sabizabulin, temozolomide, thiotepa, topotecan, vinblastine, vinorelbine, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the chemotherapeutic agent is capecitabine, carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, paclitaxel, and vinorelbine or a pharmaceutically acceptable salt thereof. In some embodiments, the chemotherapeutic agent is paclitaxel. In some embodiments, the chemotherapeutic agent is cisplatin, carboplatin or oxaliplatin. In some embodiments, the chemotherapeutic agent is carboplatin.

[0159] In some embodiments, the additional anticancer agent is an endocrine agent, such as an aromatase inhibitor (e.g., anastrozole, exemestane, fadrozole, formestane, and letrozole), a luteinizing hormone-releasing hormone (LHRH) receptor agonist (e.g., leuprolide, and leuprorelin), a Selective Estrogen-Receptor Downregulator (SERD) (e.g., amcenestrant, camizestrant, elacestrant, fulvestrant, giredestrant, imlunestrant, rintodestrant, taragarestrant, and ZB716), or a Selective Estrogen Receptor Modulator (SERM) (e.g., afimoxifene, arzoxifene, bazedoxifene, clomiphene, fispemifene, lasofoxifene, raloxifene, ormeloxifene, ospemifene, tamoxifen, tesmilifene, toremifene, and trilostane). In some embodiments, the endocrine agent is anastrozole, elacestrant, exemestane, fulvestrant, letrozole, raloxifene, tamoxifen, toremifene, or a combination thereof. In some embodiments, the additional anticancer agent is an aromataseAttorney Ref. No. 01234-0009-00PCTinhibitor. In some embodiments, the aromatase inhibitor is anastrozole, exemestane, or letrozole. In some embodiments, the aromatase inhibitor is letrozole. In some embodiments, the additional anticancer agent is a SERD. In some embodiments, the SERD is elacestrant or fulvestrant. In some embodiments, the SERD is elacestrant. In some embodiments, the SERD is fulvestrant. In some embodiments, the SERD is camizestrant.Biomarkers and Pharmacodynamics Markers

[0160] The disclosure provides predictive markers including, but not limited to, biomarkers and pharmacodynamic markers, which can be monitored based on levels including, but not limited to, DNA (including cDNA), RNA (including messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA)), protein expression (including protein overexpression), enzyme activity (e.g., for TK1), gene copy number, gene expression, gene sequence, mutations, and phosphorylation, to identify those subjects having, suspected of having, or at risk of developing a cancer for whom administering a CDK4 degrader is likely to be effective.

[0161] In some embodiments, the biomarker is selected from AR; breast cancer gene 1 (BRCA1); breast cancer gene 2 (BRCA2); cyclin Al (CCNA1); cyclin A2 (CCNA2); cyclin Bl (CCNB1); cyclin DI (CCND1); cyclin D2 (CCND2); cyclin D3 (CCND3); cyclin El (CCNE1); cyclin E2 (CCNE2); cyclin-dependent kinase 1 (CDK1); CDK2; cyclin-dependent kinase 3 (CDK3); CDK4; cyclin-dependent kinase 5 (CDK5); CDK6; cyclin-dependent kinase 18 (CDK18); cyclin-dependent kinase inhibitor 1A (CDKN1A); cyclin-dependent kinase inhibitor IB (CDKN1B); cyclin-dependent kinase inhibitor 2A (CDKN2A, also known pl 6, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, pl6-INK4a, and pl6(INK4)); ER; Harvey rat sarcoma virus proto-oncogene, GTPase (HRAS); HER2; human epidermal growth factor receptor-3 (HER3); KRAS; neuroblastoma rat sarcoma virus oncogene homolog (NRAS); PR; prostate-specific antigen (PSA); RB transcriptional corepressor 1 (RBI, which encodes retinoblastoma 1 protein referred to as Rb, RB, or RBI); retinoblastoma transcriptional corepressor like 1 (RBL1); retinoblastoma transcriptional corepressor like 2 (RBL2); thymidine kinase 1 (TK1), and the corresponding proteins encoded by these genes. In some embodiments, the biomarker is selected from AR; BRCA1; BRCA2; CCND1, CDK4, ER, HER2, pl6 (or CDKN2A), PR, PSA, RBI, TK1, and the corresponding proteins encoded by these genes.

[0162] In some embodiments, the levels of a biomarker are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, a biomarker is absent. In some embodiments, the modulation results in the loss of expression of the corresponding protein, aAttorney Ref. No. 01234-0009-00PCTdecrease in the expression of DNA (including cDNA), a decrease in the expression level of RNA (including messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA), a decrease in the expression level of protein, a decrease in gene copy numbers, a decrease in gene expression, a decrease in phosphorylated protein, or a decrease in protein activity as compared to a control sample. In some embodiments, the modulation results in an elevated expression level of DNA, an elevated expression level of RNA, an elevated expression level of protein (including protein overexpression), an increase in gene copy numbers, an increase in gene expression, an increase in phosphorylated protein, or an increase in protein activity as compared to a control sample. In some embodiments, the biomarker has a mutation (e.g., a loss of function mutation). In some embodiments, a biomarker or a biomarker mutant is functional. In some embodiments, a biomarker is intact based on expression level of mRNA or Rb and no loss of function mutations. In some embodiments, a change in the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is indicative / predictive that a subject having or at risk of developing a cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, a comparison of the amplification and / or levels of certain biomarkers is made between a biological sample (e.g., the subject’s tumor, plasmas, or other tissue) and a control sample. In some embodiments, the control sample comprises normal tissue. In some embodiments, the control sample is from a subject with a normally functioning pathway. In some embodiments, the control sample provides or a comparison is made to an average expression level (e.g., mRNA or protein) of certain biomarkers in a population of subjects suffering from a solid tumor. In some embodiments, the control sample provides or a comparison is made to an average expression level (e.g., mRNA or protein) of certain biomarkers in a population of subjects suffering from a specific cancer.

[0164] In some embodiments, the levels of a biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,Attorney Ref. No. 01234-0009-00PCT70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker before and after administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced.

[0165] In some embodiments, the levels of the biomarker at two different timepoints during treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are changed by at least 10%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during treatment are changed by about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are increased. In some embodiments, the levels of the biomarker at two different timepoints during administration of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, are reduced.

[0166] In another aspect, provided herein is a method of treating cancer in a subject in need thereof comprising:i. testing, or having tested, a first biological sample obtained from the subject with cancer, thereby measuring levels of one or more biomarkers in the subject’s tumor, plasmas, or other tissue;ii. comparing the levels of the one or more biomarkers in step i. to levels of one or more biomarkers measured in a population of subjects suffering from cancer;iii. determining that the subject’s cancer will be sensitive to a compound of the disclosure, or a pharmaceutically acceptable salt thereof;iv. administering to the subject a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, thereby treating the cancer.

[0125] In some embodiments, the method further comprises:v. further testing, or having tested, a first biological sample obtained from the subject with cancer, thereby further measuring levels of one or more additional biomarkers in the subject’s tumor, plasmas, or other tissue;Attorney Ref. No. 01234-0009-00PCTvi. testing, or having tested, a second biological sample obtained from the subject, thereby measuring levels of one or more additional biomarkers in the subject’s tumor, plasmas, or other tissue;vii. determining whether the subject having or at risk of developing cancer has responded to treatment with a compound of the disclosure, or a pharmaceutically acceptable salt thereof, if the comparison of the second biological sample analysis in step vi. to the first biological sample analysis in step v. shows a changed level of one or more biomarkers, thereby monitoring a response in a subject having or at risk of developing cancer.

[0126] In some embodiments, additional biological samples are obtained from the subject and compared to the levels of the biomarkers measured in a patient with a control level to continue monitoring. In some embodiments, additional biological samples are obtained from the patient and compared to the levels of the biomarkers measured in the first biological sample to continue monitoring.

[0127] In some embodiments, the biomarker is AR. AR, a ligand-dependent nuclear transcription factor and member of the steroid hormone nuclear receptor family, mediates the actions of androgens such as testosterone and dihydrotestosterone. In some embodiments, the cancer is breast cancer or prostate cancer. In some embodiments, the breast cancer or prostate cancer is characterized by the presence of AR or an elevated level of AR and / or AR splice variants, such as AR-V7, compared to a control level of AR. In some embodiments, the levels of AR and / or AR splice variants, such as AR-V7, are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, AR and / or AR splice variants, such as AR-V7, are biomarkers for sensitivity to a compound of the disclosure.

[0128] In some embodiments, the biomarker is BRCA1 or BRCA2. BRCA1 and BRCA2 protein have crucial roles in different cellular processes, including transcriptional regulation, cell cycle checkpoints regulation, mitophagy, and DNA repair, such as regulating homologous recombination-dependent DNA double strand break repair. In some embodiments, mutations in the BRCA1 gene or the BRCA2 gene predispose a subject to cancer. In some embodiments, the cancer is bile duct cancer, breast cancer, or prostate cancer.

[0129] In some embodiments, the biomarker is CCND1. Cyclin DI modulates the transition from G1 to S phase as an allosteric regulator of CDK4 and CDK6. In some embodiments, the cancer is bladder cancer, cholangiocarcinoma, esophageal cancer, gastric cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, HR+ / HER2- breast cancer, non-small cellAttorney Ref. No. 01234-0009-00PCTlung cancer, or small cell lung cancer. In some embodiments, these cancers are characterized by an elevated level of CCND1 compared to a control level of CCND1.

[0130] In some embodiments, the biomarker is ER and / or PR. Hormone receptor proteins, including ER, which is activated by estrogen, and PR, which is activated by progesterone, are nuclear transcription factors involved in the regulation of many physiological processes, including promoting cell growth. In some embodiments, the breast cancer is characterized by the presence of ER and / or PR. In some embodiments, the breast cancer is characterized by an elevated level of ER and / or PR compared to a control level of ER and / or PR. In some embodiments, the levels of ER and / or PR are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, ER and / or PR are biomarkers for sensitivity to a compound of the disclosure.

[0131] In some embodiments, the biomarker is HER2. HER2 is an epidermal growth factor receptor having tyrosine kinase activity. In some embodiments, the HR+ / HER2- breast cancer or small-cell lung cancer is characterized by the absence of HER2. In some embodiments, the HR+ / HER2- breast cancer or small-cell lung cancer is characterized by a reduced level of HER2 compared to a control level of HER2. In some embodiments, the level of HER2 is modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, HER2 is a biomarker for sensitivity to a compound of the disclosure.

[0132] In some embodiments, the biomarker is pl6 (also known as cyclin-dependent kinase inhibitor 2 A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, pl6-INK4a, and pl6(INK4)). The gene CDKN2A encodes pl 6, which acts as a negative regulator of the proliferation of normal cells by interacting with CDK4 and CDK6. In some embodiments, the level of pl6 is modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, pl6 is a biomarker for sensitivity to a compound of the disclosure.

[0133] In some embodiments, the biomarker is retinoblastoma 1 protein (Rb, RB, or TB1), which is encoded by the gene RB transcriptional corepressor 1 (RBI). Rb is a regulator of the cell cycle and acts as a tumor suppressor. In some embodiments, the cancer is characterized by the presence of Rb. In some embodiments, the cancer is characterized by the absence of Rb.

[0134] In some embodiments, the biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at the serine corresponding to amino acid position 780 (Ser780 or S780) and / or the serine corresponding toAttorney Ref. No. 01234-0009-00PCTamino acid position 795 (Ser795 or S795). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the serine corresponding to amino acid position 807 (Ser807 or S807) and / or the serine corresponding to amino acid position 811 (Ser811 or S811). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 821 (Thr821 or T821). In some embodiments, the contemplated biomarker is phosphorylation of Rb at the threonine corresponding to amino acid position 826 (Thr826 or T826). Rb is activated upon phosphorylation by cyclin D-CDK4 / 6 at Ser780 and Ser795 and / or at Ser807 and / or Ser811 and by cyclin E / CDK2 at Ser807 and Ser811 and Thr821. In some embodiments, the levels of phosphorylated Rb, Rb, or RB are modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, phosphorylated Rb, Rb, or RB is a biomarker for sensitivity to a compound of the disclosure. In some embodiments, the levels of phosphorylated Rb are reduced compared to a control level of phosphorylated Rb.

[0135] In some embodiments, the biomarker is PSA. PSA, which is a serine protease human kallikrein 3, plays a role in the regulation of semen coagulation. In some embodiments, the cancer is prostate cancer characterized by an elevated level of PSA compared to a control level of PSA.

[0136] In some embodiments, the biomarker is TK1. TK1 is a direct downstream target of Rb-E2F pathway. It is involved in cellular proliferation through the recovery of the nucleotide thymidine in the DNA salvage pathway. TK1 is important for DNA repair following DNA damage because TK1 is necessary for the formation of nucleotides outside of the S phase. In some embodiments, the level of TK1 is modulated in response to administration of an effective dose of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, to a subject. In some embodiments, TK1 is differentially methylated. In some embodiments, TK1 is serum TK1. In some embodiments, the levels of TK1 protein and / or enzyme activity are reduced compared to a control level of TK1 protein and / or enzyme activity. In some embodiments, TK1 is a biomarker for sensitivity to a compound of the disclosure.EXAMPLES

[0137] The following Examples are presented by way of illustration, not limitation.Compounds are named using the automatic name generating tool provided in ChemBioDraw Ultra (Cambridgesoft), which generates systematic names for chemical structures, with support for the Cahn-Ingold-Prelog rules for stereochemistry. One skilled in the art can modify the procedures set forth in the illustrative examples to arrive at the desired products.Attorney Ref. No. 01234-0009-00PCT

[0138] Salts of the compounds described herein can be prepared by standard methods, such as inclusion of an acid (for example, TFA, formic acid, or HC1) in the mobile phases during chromatography purification, or stirring of the products after chromatography purification, with a solution of an acid (for example, aqueous HC1).Abbreviations

[0139] The following abbreviations may be relevant for this application.ACN or acetonitrile AcOH acetic acidMeCNaq. aqueous BINAP (±)-2,2'-Bis(diphenyl- phosphino)-l,l'- binaphthaleneBn benzyl Boc tert-butoxy carbonyl BOC2O di-tert-butyl decarbonate Brettphos or 2-(dicyclohexylphosphino)- BrettPhos 3,6-dimethoxy-2',4',6'- triisopropyl- 1, 1 '-biphenyl Brettphos Pd (SP-4-3)-[Dicyclohexyl[3,6- / -B11OH or tert-butanolG4 or dimethoxy-2',4',6'-tris(l- ‘BuOHBrettPhos Pd methylethyl) [1,1 '-biphenyl] -2- G4yl]phosphine-KP](methane- sulfonato-KO)[2'-(methylamino- K2V)-[ 1, 1 '-biphenyl] -2-yl-KQt-BuONa sodium tert-butoxide n-BuLi n-butyl lithium°C degrees Celsuis CAN Cerium ammonium nitrate CBz carboxybenzyl CDI 1,1’ -carbonyldiimidazole CDCh deuterated chloroform 5 chemical shiftDABCO 1,4-diazabicyclooctane DCM dichloromethaneDIEA or N-ethyldiisopropylamine or dioxane 1,4-dioxaneDIPEA N, N-diisopropylethylamineDMA N, N -dimethylacetamide DMF dimethylformamide DMSO dimethylsulfoxide DMSO-d6hexadeuterodimethyl sulfoxideEt ethyl Et₃N or triethylamineTEAEtOAc ethyl acetate EtOH ethanolequiv. equivalent(s) g gramor eq.h hour(s) HATU O-(7-azabenzotriazol- 1 -yl)- N, N, N', N’- tetramethyluronium hexafluorophosphate HPLC high pressure liquid IBX 2-iodoxybenzoic acid chromatographyIPA 2-propanol or isopropanol Ir[dF(CF3)ppy]2 [4,4 '-Bis( 1, 1 -dimethylethyl)- (dtbpy)(PF6) 2,2'-bipyridine- M, Al']M3,5-difluoro-2-[5- (trifluoromethyl)-2- pyridinyl-A'|phcnyl- C]Iridium(III)hexafluorophosphateAttorney Ref. No. 01234-0009-00PCTIr(ppy)2(dtbpy) [4,4 '-Bis( 1, 1 -dimethylethyl) - KOAc potassium acetate (PF6) 2,2'-bipyridine-AlA4']6z.s'[2-(2- pyridinyl-JV)phenyl- C] iridium (III)hexafluorophosphateKOtBu potassium tert-butoxide L literLAH lithium aluminum hydride LCMS liquid chromatography-mass spectrometry LiHMDS lithium bis(trimethylsilyl)amide M MolarMe methyl Mel iodomethaneMeOH methanol MeOH-d4deuterated methanol CDsOHmg milligram(s) MHz mega Hertzmin minute(s) mL milliliter(s)mmol millimole(s) m / z mass to charge ratio 4A MS or 4A 4A molecular sieves NaBH(OAc)3sodium triacetoxyboroMS hydrideNaHMDS sodium bis(trimethylsilyl)amide NHC-1 N-heterocyclic carbene NMR nuclear magnetic resonance Pd2(dba)3tris(dibenzylideneacetone)- (spectroscopy) dipalladium (0) Pd(dppf)Cl2[1,1 '-Bis(diphenylphosphino)- Pd-PEPPSI- palladium(II) l,3-bis[2,6- ferrocene]dichloropalladium(II) IHeptCl bis(heptan-4-yl)phenyl]-4,5- dichloro- 1,2-didehydro- 1 X5- imidazole 3 -chloropyridine dichloride Pd(PPh3)2Cl2bis(triphenylphosphine) PE petroleum ether palladium(II) dichloridePFA perfluoroalkoxyalkane PMB p-methoxybenzyl prep-TLC preparative thin layer Py pyridine chromatographyRuPhos 2-dicyclohexylphosphino-2',6'- RuPhos Pd G2 chloro(2-dicyclohexyl- diisopropoxybiphenyl phosphino-2',6'- diisopropoxy-1,1'- biphenyl) [2-(2'-amino- 1,1'- biphenyl)]palladium(II) RuPhos Pd G3 (2-dicyclohexylphosphino-2',6'- rt room temperature diisopropoxy- 1, 1 '-biphenyl) [2- (2'-amino- 1, 1 '-biphenyl)] - palladium(II) methane sulfonateRT or Rt retention time sat. saturatedSEM trimethylsilylethoxymethyl SFC supercritical fluid chromatographySTAB sodium triacetoxyborohydride TBAF tetra-n-butylammonium fluorideTEA triethylamine TFA trifluoroacetic acid Tf2O trifluoromethane sulfonic TfOH trifluoromethanesulfonic anhydride acid or triflic acid THF tetrahydrofuran TLC thin layer chromatography TMSC1 trimethylsilyl chloride pL microliter(s)pmol micromole(s) XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxantheneGeneral MethodsAttorney Ref. No. 01234-0009-00PCT

[0140] Proton NMR:1H NMR spectra were obtained with a Varian 400MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds with a 1 second delay; 16 to 64 scans). Where characterized, all protons were reported in DMSO-d₆ solvent as parts-per million (ppm) with respect to residual DMSO (2.50 ppm); or where characterized, all protons were reported in CD₃OD solvent as parts-per million (ppm) with respect to residual CD₃OD (3.31 ppm); or where characterized, all protons were reported in CDCl₃ solvent as parts-per million (ppm) with respect to residual CDCl₃ (7.27 ppm); or where characterized, all protons were reported in D2O solvent as parts-per million (ppm) with respect to residual D2O (4.79 ppm).

[0141] Silica gel chromatography: Silica gel chromatography was performed on a Biotage® Isolera unit.

[0142] SFC: Chiral SFC was performed on a Waters SFC 80Q or Waters SFC 150Mgm or Waters SFC 350 or Hanbon SFC 600 system using Shimadzu LC-30Ads.

[0143] LC-MS: liquid chromatography-mass spectrometry (LC-MS) data (sample analyzed for purity and identity) were obtained with

[0144] A) an Agilent model-1260 LC system using an Agilent model 6120 mass spectrometer utilizing ES-API ionization fitted with a Kinetex EVO C18 30*2.1 mm, 5 pm reverse-phase column at 50 °C. The flow rate was constant at 1.5 mL / min.

[0145] B) Shimadzu LCMS system using a Shimadzu LCMS mass spectrometer utilizing ESI ionization fitted with a Halo 90A C18 30*3.0 mm, 5um or Kinetex EVO C18 30*2.1 mm, 5 pm reverse-phase column at 50 °C. The flow rate was constant at 1.5 mL / min.

[0146] Analytical HPLC: HPLC was performed on a Shimadzu Preparative system fitted with a Kinetex C18 LC Column 4.6 X 50 mm reverse-phase column at 50 °C. The flow rate was constant at 1.5 mL / min.

[0147] Preperative HPLC: HPLC was performed on a Gilson Preparative system fitted with the columns as described below to purify the Intermediates and Examples, where the HPLC conditions were optimized for each compound as required. Conditions reported in the documents as HPLC-code (% MeCN). The flow rate was constant at 25 mL / min.HPLC DetailsCode1 Phenomenex Luna C18 150 x 25 mm, 10 pm; 0-100% MeCN / H2O (0.1% HCO2H) 2 Phenomenex Luna C18250 x 70 mm, 10 mm; 0-100% MeCN / H2O (0.1% HCO2H) 3 Phenomenex Luna C18 150 x 25 mm, 10 mm; 0-100% MeCN / H2O (TFA)4 UniSil 3-100 C18 Ultra 150 x 50 mm, 3 mm; 0-100% MeCN / H2O (HCO2H)5 Waters Xbridge 150 x 25 mm, 10 mm; 0-100% MeCN / H2O (NH4HCO3)6 Waters Xbridge 150 x 25 mm, 5 mm; 0-100% MeCN / H2O (NH4HCO3)Attorney Ref. No. 01234-0009-00PCTWaters Xbridge 150 x 50 mm, 10 mm; 0-100% MeCN / H2O (NH4HCO3)Welch Xtimate Cl 8 150 x 25 mm, 5 mm; 0-100% MeCN / H2O (HCO2H)HPLC DetailsCode1* Phenomenex Luna C18 150 x 25 mm, 10 mm; 0-100% MeCN / H2O (0.1% HCO2H) 2* Phenomenex Luna C18 150 x 25 mm, 10 mm; 0-100% MeCN / H2O (0.1% TFA) 3* UniSil 3-100 C18 Ultra 150 x 50 mm, 3 mm; 0-100% MeCN / H2O (0.225% HCO2H) 4* Waters Xbridge 150 x 25 mm, 10 mm; 0-100% MeCN / H2O (NH4HCO3)5* Waters Xbridge 150 x 25 mm, 5 mm; 0-100% MeCN / H2O (NH4HCO3)6* Waters Xbridge 150 x 50 mm, 10 mm; 0-100% MeCN / H2O (NH4HCO3)7* Welch Xtimate C18 150 x 25 mm, 5 mm; 0-100% MeCN / H2O (HCO2H)8* Phenomenex Luna C18 150 x 25 mm, 10 mm; 0-100% MeCN / H2O (0.225% HCO2H)9* Boston Green ODS 150 x 30mm x 5um; MeCN / H2O (0.225% HCO2H)Intermediates

[0167] Intermediate 1. N, N-dimethylpropiolamide.

[0168] To a solution of N-methylmethanamine (2 M, 42.8 mL) in dichloromethane (120 mL) was added 4-dimethylaminopyridine (1.05 g, 8.57 mmol) andN, N-dicyclohexyl carbimide (17.7 g, 85.7 mmol). Propiolic acid (6.00 g, 85.7 mmol) was added to the reaction mixture at 0 °C and stirred at 20 °C for 12 h. The reaction mixture was diluted with di chloromethane (80 mL) and filtered. The filtrate was evaporated to dryness and the residue purified by silica gel chromatography (ISCO®; 80 g SepaFlash®, 45-47% EtOAc / PE) to give the title compound as a pink solid (7.30 g, 87%).1H NMR (400 MHz, CDCl3) δ: 3.22 (s, 3H), 3.12 (s, 1H), 2.97 (s, 3H).

[0169] Intermediate 2. 2-chloro-7-isopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0170] Step 1. Synthesis of 2-chloro-5-iodo-N-isopropylpyrimidin-4-amine.Attorney Ref. No. 01234-0009-00PCT

[0171] To a solution of 2,4-dichloro-5-iodopyrimidine (3.00 g, 10.91 mmol) and isopropylamine (645 mg, 10.91 mmol) in acetonitrile (20 mL) was added DIPEA (2.82 g, 21.83 mmol) and the reaction mixture stirred at 60 °C for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3x 100 mL). The combined organics was washed with brine (2x 30 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (50% EtOAc / PE) to give the title compound as a yellow solid (2.20 g, 68%). LCMS m / z = 298 [M+H]+.

[0172] Step 2. Synthesis of 3-(2-chloro-4-(isopropylamino)pyrimidin-5-yl)-N, N-dimethylpropiolamide.

[0173] A mixture of 2-chloro-5-iodo-N-isopropylpyrimidin-4-amine (Step 1, 2.20 g, 7.39 mmol), N, N-dimethylpropiolamide (Intermediate 1, 718 mg, 7.39 mmol), Pd(PPh3)2Ch (519 mg, 739.4 pmol), DIPEA (1.91 g, 14.8 mmol) and copper iodide (141 mg, 739.44 pmol) in DMF (20 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 80 °C for 2 h under nitrogen. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3x lOOmL). The combined organic layers were washed with brine (2x 30 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by silica gel chromatography (50% EtOAc / PE) to give the title compound as a yellow solid (1.20 g, 61%). LCMS m / z = 267 [M+H]+.

[0174] Step 3. Synthesis of 2-chloro-7-isopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0175] To a solution of 3-(2-chloro-4-(isopropylamino)pyrimidin-5-yl)-N, N-dimethylpropiolamide (Step 3, 300 mg, 1.12 mmol) in DMSO (4 mL) was added cesium carbonate (733 mg, 2.25 mmol) and the mixture stirred at 30 °C for 16 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc / PE) to give the title compound as a yellow solid (140 mg, 47%). LCMS m / z = 267 [M+H]+.

[0176] Intermediate 3. (R)-2-chloro-7-(l-hydroxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Attomey Ref. No. 01234-0009-00PCT

[0177] Step 1. Synthesis of (R)-2-((2-chloro-5-iodopyrimidin-4-yl)amino)propan-l-ol.

[0178] To a solution of 2,4-dichloro-5-iodopyrimidine (2.00 g, 7.28 mmol) and (R)-2-aminopropan- l-ol, (492 mg, 6.55 mmol) in MeCN (20 mL) was added DIPEA (14.6 mmol, 2.53 mL) and the mixture stirred at 60 °C for 1 h. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (2x 30 mL), dried (ISfeSCU) and evaporated to dryness under reduced pressure. The residue was purified by prep-HPLC-2 (10-50% MeCN) to give the title compound as a white solid (1.50 g, 66%). 'H NMR (400MHz, DMSO-d6): 8.28 (s, 1H), 5.65 (d, 1H), 4.49-4.26 (m, 1H), 3.81 (dd, 1H), 3.68 (dd, 1H), 2.19 (s, 1H), 1.32 (d, 3H).

[0179] Step 2. Synthesis of (R)-3-(2-chloro-4-((l-hydroxypropan-2-yl)amino)-pyrimidin-5-yl)-N, N-dimethylpropiolamide.

[0180] A mixture of (R)-2-((2-chloro-5-iodopyrimidin-4-yl)amino)propan-l-ol (Step 1, 1.40 g, 4.47 mmol), N, N-dimethylpropiolamide (Intermediate 1, 867 mg, 8.93 mmol), Pd(PPh3)2Ch (313 mg, 447 pmol), Cui (85.0 mg, 447 pmol) and DIPEA (13.4 mmol, 2.33 mL) in DMF (25 mL)was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 80 °C for 2 h under nitrogen. The reaction mixture was diluted with water (200 mL) and extracted with EtOAc (3x 150 mL). The combined organics were washed with brine (2x 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-50% EtOAc / PE) to give the title compound as a yellow solid (1.20 g, 95%). LCMS m / z = 283 [M+H]+.

[0181] Step 3. Synthesis of (R)-2-chloro-7-(l-hydroxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0182] To a solution of (R)-3-(2-chloro-4-((l-hydroxypropan-2-yl)amino)pyrimidin-5-yl)-N, N-dimethylpropiolamide (Step 2, 100 mg, 354 pmol) in DMSO (3 mL) was added cesium carbonate (230 mg, 707 pmol) and the mixture stirred at 30 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 20 mL). The combined organicsAttorney Ref. No. 01234-0009-00PCTwas washed with brine (2x 20 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by prep-TLC (SiO2, 75% EtOAc / PE) to give the title compound as a yellow solid (40 mg, 40%). LCMS m / z = 283 [M+H]+.

[0183] Intermediate 4. 2-chloro-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Cl ClStep 3

[0184] Step 1. Synthesis of 2-chloro-N-cyclopropyl-5-iodopyrimidin-4-amine.

[0185] To a solution of 2,4-dichloro-5-iodopyrimidine (2.00 g, 7.28 mmol) and cyclopropylamine (415 mg, 7.28 mmol) in MeCN (30 mL) was added DIPEA (14.5 mmol, 2.53 mL) and the mixture stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (60 mL) and extracted with EtOAc (3x 60 mL). The combined organics were washed with brine (3x 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 15-25% EtOAc / PE) to give the title compound as a white solid (1.70 g, 79%). LCMS m / z = 295 [M+H]+.

[0186] Step 2. Synthesis of 3-(2-chloro-4-(cyclopropylamino)pyrimidin-5-yl)-N, N-dimethylpropiolamide.

[0187] A mixture of 2-chloro-N-cyclopropyl-5-iodopyrimidin-4-amine (1.00 g, 3.38 mmol), N, N-dimethylpropiolamide (Intermediate 1, 492 mg, 5.08 mmol), Cui (32.2 mg, 169 pmol), DIPEA (6.77 mmol, 1.18 mL) and Pd(PPh3)2Cl2(237 mg, 338 pmol) in DMF (10 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 80 °C for 2 h. The residue mixture was diluted with water (60 mL) and extracted with EtOAc (3x 60 mL). The combined organics were washed with brine (3x 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15-25% EtOAc / PE) to give the title compound as a white solid (800 mg, 89%). LCMS m / z = 265[M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0188] Step 3. Synthesis of 2-chloro-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0189] To a solution of 3-(2-chloro-4-(cyclopropylamino)pyrimidin-5-yl)-N, N-dimethylpropiolamide (Step 3, 800 mg, 3.02 mmol) in DMSO (10 mL) was added CS2CO3 (1.97 g, 6.04 mmol) and the mixture stirred at 25 °C for 12 h. The mixture was purified directly without work up and purified by reverse-phase (0.1% TFA condition) to give the title compound as a white solid (800 mg, 89%). LCMS m / z = 265 [M+H]+.

[0190] Intermediate 5. (rac)-7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0191] Step 1. Synthesis of (rac)-N-((lR,2R, 4S)-bicyclo[2.2. l]heptan-2-yl)-2-chloro-5-iodopyrimidin-4-amine.

[0192] To a solution of (rac)-(lR,2R,4S)-bicyclo[2.2.1]heptan-2-amine hydrochloride (3.00 g, 20.3 mmol) in dioxane (30 mL) was added TEA (6.17 g, 61.0 mmol) and 2,4-dichloro-5-iodopyrimidine (6.70 g, 24.4 mmol) and the reaction mixture stirred at 40 °C for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (3x 20 mL). The combined organics was dried (Na2SO4) and evaporated to dryness. The residue was purified by silica gel chromatography (ISCO®; 80 g SepaFlash®; 12-14% EtOAc / PE) to give the title compound as a light yellow oil (5.50 g, 75%). LCMS m / z = 350 [M+H]+.

[0193] Step 2. Synthesis of (rac)-3-(4-(((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloropyrimidin-5-yl)-N, N-dimethylpropiolamide.

[0194] A mixture of (rac)-N-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-5-iodopyrimidin-4-amine (Step 1, 1.50 g, 4.29 mmol), N, N-dimethylpropiolamide (Intermediate 1, 625 mg, 6.44 mmol), Cui (81.7 mg, 429 pmol), DIPEA (1.66 g, 12.9 mmol) and Pd(PPh3)2Ch (150 mg, 215 pmol) in DMF (20 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 80 °C for 2 h under nitrogen. The reaction mixture was diluted withAttorney Ref. No. 01234-0009-00PCTEtOAc (40 mL) and filtered. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2x 20 mL). The combined organics were washed with saturated brine (4x 30 mL), dried (Na2SC>4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 40 g SepaFlash®, 60-62% EtOAc / PE) to give the title compound as a light yellow solid (850 mg, 60%). LCMS m / z = 319 [M+H]+.

[0195] Step 3. Synthesis of (rac)-7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0196] To a solution of (rac)-3-(4-(((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)amino)-2-chloropyrimidin-5-yl)-N, N-dimethylpropiolamide (Step 2, 750 mg, 2.35 mmol) in DMSO (15 mL) was added cesium carbonate (1.53 g, 4.71 mmol) and the reaction mixture stirred at 50 °C for 16 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3x 5 mL). The combined organics were washed with saturated brine (4x 5 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by silica gel chromatography (ISCO®; 12 g SepaFlash®, 49-50% EtOAc / PE) to give the title compound as a yellow solid (600 mg, 80%). LCMS m / z = 319 [M+H]+.

[0197] Intermediate 6 and 7. 7-((lS,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and 7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0198] (rac)-7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide was separated by SFC (Diacel Chiralpak AD, 250 x 30 mm, 10 mm; 15% EtOH (0.1% NH4OH) in CO2 to afford:

[0199] Peak 1, Intermediate 6 as an off-white solid (270 mg, 40%). 7-((lS,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 319 [M+H]+.

[0200] Peak 2, Intermediate 7 as an off-white solid (320 mg, 48%). 7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((l S,2S,4R)-bicyclo[2.2. l]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 319 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0201] Intermediate s and 9. 7-((lS,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and 7-((lR,2S,4S)-bicyclo[2.2. l]heptan- 2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0202] (rac)-7-((l S,2R,4R)-bicyclo[2.2. l]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide was separated by SFC (Diacel Chiralpak AD-3, 50 x 4.6 mm, 3 mm; 5-40% EtOH (0.05% DEA) in CO2 to afford:

[0203] Peak 1, Intermediate 8 as a yellow solid (260 mg, 40%). 7-((lS,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide LCMS m / z = 319 [M+H]+.

[0204] Peak 2, Intermediate 9 as a white solid (300 mg, 46%). 7-((lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((l S,2R,4R)-bicyclo[2.2. l]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 319 [M+H]+.

[0205] Intermediate 10 and 11. (S)-7-(bicyclo[2.1.1]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and (R)-7-(bicyclo[2.1. l]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0206] (rac)-7-(bicyclo[2.1.1]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 21, 80 mg, 0.262 mmol) was separated SFC ((s,s)-WHELK-01, 250 x 50 mm, 10 mm; 32% EtOH (0.1% NH4OH) in CO2) to give:

[0207] Peak 1, Intermediate 10 as a white solid (40 mg, 48%). (S)-7- (bicyclo[2.1. l]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or (R)-7-(bicyclo[2.1. l]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 305 [M+H]+.

[0208] Peak 2, Intermediate 11 as a white solid (40 mg, 47%). (R)-7- (bicyclo[2.1. l]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideAttorney Ref. No. 01234-0009-00PCTor (S)-7-(bicyclo[2.1. l]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 305 [M+H]+.

[0209] Intermediate 12. 7-(bicyclo[2.1.1]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0210] Step 1. Synthesis of 3-((dimethylamino)methylene)bicyclo[2.2.1 ]heptan-2-one.

[0211] A mixture of bicyclo[2.2.1]heptan-2-one (9.00 g, 81.7 mmol) and 1-tert-butoxy-N, N, N', N' -tetramethylmethanediamine (14.9 g, 85.7 mmol) was stirred at 80 °C for 16 h under nitrogen. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography (8:1 PE / EtOAc) to give the title compound as a yellow oil (13.5 g, 90%).

[0212] Step 2. Synthesis of 3-diazobicyclo[2.2.1 ]heptan-2-one.

[0213] To a solution of 3-((dimethylamino)methylene)bicyclo[2.2.1]heptan-2-one (Step 1, 13.5 g, 81.7 mmol) in THF (200 mL) was added 4-dodecylbenzenesulfonyl azide (31.5 g, 89.8 mmol) and the reaction mixture stirred at 40 °C for 12 h. The reaction mixture was evaporated to dryness and the residue purified by silica gel chromatography (5:1 PE / EtOAc) to give the title compound as a yellow oil (9.00 g, 73%).1H NMR (400 MHz, CDCl3) δ: 3.50 (s, 1H), 2.74-2.69 (m, 1H), 1.99-1.62 (m, 5H), 1.48 (d, 1H).

[0214] Step 3. Synthesis of bicyclo[2.1.1]hexane-5-carboxylic acid.

[0215] To a solution of 3-diazobicyclo[2.2.1]heptan-2-one (Step 2, 6.90 g, 50.6 mmol) in THF (240 mL) and water (240 mL) was added sodium bicarbonate (8.51 g, 101 mmol) and the reaction mixture pumped through a flow reactor with 60 min residence time with 365 nm LED light at 25 °C. The reaction mixture was concentrated in vacuo to remove THF and the aqueous phase extracted with EtOAc (2x 50 mL). The combined organics were discarded and the aqueous phase acidified with 1 mol / L aqueous hydrochloric acid to pH = 3 and extracted with EtOAc (4x 80 mL). The combined organics were washed with brine (2x 50 mL), driedAttorney Ref. No. 01234-0009-00PCT(Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (10:1 PE / EtOAc) to give the title compound as a yellow oil (1.98 g, 31%).1H NMR (400 MHz, CDCl3) δ: 2.81 (d, 0.4H), 2.78 (t, 2H), 2.53 (s, 1H), 2.35-2.30 (m, 0.2H), 2.27 (d, 0.2H), 1.83-1.77 (m, 2H), 1.76-1.69 (m, 4 x 0.2H), 1.63-1.56 (m, 2H), 1.46 (td, 1H), 1.07 (t, 0.2H), 0.83 (d, 1H).

[0216] Step 4. Synthesis of benzyl bicyclo[2.1.1]hexan-5-ylcarbamate.

[0217] To a solution of bicyclo[2.1.1]hexane-5-carboxylic acid (Step 3, 2.30 g, 18.2 mmol) and 4A MS (2.00 g) in toluene (30 mL) and benzyl alcohol (30 mL) was added TEA (3.69 g, 36.4 mmol) and diphenyl phosphorazidate (7.53 g, 27.3 mmol) at 20 °C. The reaction mixture was stirred at 100 °C for 12 h, filtered and the filter cake washed with EtOAc (30 mL). The combined organics were evaporated to dryness under reduced pressure and the residue diluted with water (60 mL) and extracted with etOAc (4x 80 mL). The combined organics were washed with brine (2x 50 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by silica gel chromatography (20:1 PE / EtOAc) to give the title compound as a colourless oil (2.65 g, 62%).1H NMR (400 MHz, CDCl3) δ: 7.42-7.30 (m, 5H), 5.20-4.99 (m, 2H), 4.76-4.33 (m, 1H), 3.65-3.38 (m, 1H), 2.62-2.44 (m, 2H), 1.66-1.56 (m, 2H), 1.54-1.36 (m, 2H), 1.27-1.20 (m, 1H), 0.75 (d, 1H).

[0218] Step 5. Synthesis of bicyclo[2.1.1]hexan-5-amine hydrochloride.

[0219] To a solution of Pd(OH)2 (0.50 g, 534 pmol, 15% purity) and Pd / C (0.50 g, 469 pmol, 10% purity) in ethyl acetate (40 mL) was added benzyl bicyclo[2.1.1]hexan-5-ylcarbamate (Step 4, 2.80 g, 12.1 mmol) and the reaction mixture stirred at 25 °C for 12 h under hydrogen (50 psi). The reaction mixture was diluted with methanol (40 mL) and filtered. The filtrate was acidified with 4 mol / L hydrochloride in dioxane till pH = 2, and concentrated in vacuo to give the title compound as a white solid (1.90 g, crude).1H NMR (400 MHz, DMSO-d6) 6: 7.95 (s, 3H), 2.99 (d, 1H), 2.57-2.54 (m, 2H), 1.69-1.49 (m, 4H), 1.36-1.15 (m, 1H), 0.90-0.60 (m, 1H).

[0220] Step 6, 7, 8. Synthesis of 7-(bicyclo[2.1.1]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0221] The title compound was prepared as a yellow solid from bicyclo[2.1.1]hexan-5-amine hydrochloride (Step 5) and 2,4-dichloro-5-iodopyrimidine using an analogous 3-Step method as described for Intermediate 2. 'H NMR (400 MHz, CDCI3) 6: 8.91-8.80 (m, 1H), 6.68-6.50 (m, 1H), 4.20-4.10 (m, 1H), 3.24-3.20 (m, 2H), 3.17 (d, 6H), 1.65-1.51 (m, 3H), 1.22-1.11 (m, 2H), 1.07 (d, 1H)Attorney Ref. No. 01234-0009-00PCT

[0222] Intermediate 13 and 14. 7-((lR,4S,5s)-bicyclo[2.1.1]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and 7-((lR,4S,5r)-bicyclo[2.1.1]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0223] 7-(bicyclo[2. Ll]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 12, 1.00 g mg, 3.28 mmol) was separated SFC (Diacel Chiralpak, 250 x 30 mm, 10 mm; 50% EtOH (0.1% NH4OH) in CO2) to give:

[0224] Peak 1, Intermediate 13 as a yellow solid (750 mg, 74%). 7-((lR,4S,5s)-bicyclo[2.1. l]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,4S,5r)-bicyclo[2.1.1]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 305 [M+H]+.1H NMR (400 MHz, CDCl3) δ ppm 8.78 (s, 1H), 6.55 (s, 1H), 4.18-4.13 (m, 1H), 3.21 (s, 2H), 3.16 (d, J= 11.6 Hz, 6H), 1.63-1.51 (m, 3H), 1.22-1.13 (m, 2H), 1.05 (d, J= 7.6 Hz, 1H).

[0225] Peak 2, Intermediate 14 as a yellow solid (110 mg, 9%). 7-((lR,4S,5r)-bicyclo[2.1. l]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,4S,5s)-bicyclo[2.1.1]hexan-5-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide. LCMS m / z = 305 [M+H]+.1H NMR (400 MHz, CDCI3) 8 ppm 8.81 (s, 1H), 6.61 (s, 1H), 4.13 (d, J= 7.2 Hz, 1H), 3.37 (d, J= 2.4 Hz, 2H), 3.16 (d, J= 9.2 Hz, 6H), 1.94-1.87 (m, 2H), 1.86-1.81 (m, 1H), 1.80-1.73 (m, 2H), 1.18 (t, J= 7.2 Hz, 1H).

[0226] Intermediate 15. 2-chloro-7-((lS,2R)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0227] Step 1. Synthesis of tert-butyl ((IS, 2R)-2-fluorocyclopentyl)carbamate.Attorney Ref. No. 01234-0009-00PCT

[0228] A mixture of (lS,2S)-2-((tert-butoxycarbonyl)amino)cyclopentane-l-carboxylic acid (5.00 g, 21.8 mmol,), Selectfluor (15.5 g, 43.6 mmol,), Ir[dF(CF3)ppy]2(dtbpy)(PFe) (245 mg, 218 pmol), sodium hydrogen phosphate (12.4 g, 87.2 mmol) in MeCN (120 mL) and water (120 mL) was degassed and purged with nitrogen (x3). The reaction mixture was irradiated with a 455 nm blue LED at 25 °C for 16 h under nitrogen. The reaction mixture was adjusted pH = 7 by addition sodium bicarbonate at 25 °C and extracted (EtOAc) (3x 50 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-10% EtOAc / PE) to give the title compound as a white solid (300 mg, 6%). 'H NMR (400MHz, DMSO-d6): 6.86 (d, 1H), 4.95-4.71 (m, 1H), 3.78-3.57 (m, 1H), 1.97-1.50 (m, 6H), 1.38 (s, 9H).

[0229] Step 2. Synthesis of (lS,2R)-2-fluorocyclopentan-l-amine hydrochloride.

[0230] To a solution of tert-butyl ((lS,2R)-2-fluorocyclopentyl)carbamate (Step 1, 300 mg, 1.48 mmol) in DCM (2 mL) was added hydrochloride acid / dioxane (2 mol / L, 2.00 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a white solid (205 mg, crude).1H NMR (400MHz, DMSO-d6): 8.34 (s, 3H), 5.20-4.99 (m, 1H), 3.55-3.40 (m, 1H), 2.03-1.59 (m, 7H).

[0231] Step 3. Synthesis of 2-chloro-N-((lS,2R)-2-fluorocyclopentyl)-5-iodopyrimidin-4-amine.

[0232] To a solution of (1 S,2R)-2-fluorocy cl opentan- 1 -amine hydrochloride (205 mg, 1.47 mmol) and 2,4-dichloro-5-iodopyrimidine (404 mg, 1.47 mmol) in MeCN (5 mL) was added DIPEA (380 mg, 2.94 mmol) and the reaction mixture stirred at 60 °C for 2 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure and the residue purified by column chromatography (SiC>2, 0-20%) to give the title compound as a white solid (280 mg, 54%). LCMS m / z = 342 [M+H]+.

[0233] Step 4. Synthesis of 3-(2-chloro-4-(((lS,2R)-2-fluorocyclopentyl)amino)-pyrimidin-5-yl)-N, N-dimethylpropiolamide.

[0234] A mixture of 2-chloro-N-((lS,2R)-2-fluorocyclopentyl)-5-iodopyrimidin-4-amine (Step 3, 280 mg, 820 pmol), N, N-dimethylpropiolamide (Intermediate 1, 159 mg, 1.64 mmol), Pd(PPh3)2C12 (58.0 mg, 82.0 pmol), copper iodide (8.00 mg, 41.0 pmol) and DIPEA (212 mg, 1.64 mmol) in DMF (6 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 80 °C for 2 h under nitrogen. The reaction mixture was quenched by addition water (20 mL) at 25 °C and extracted with DCM (5x 20 mL). The combined organics were washed with water (2x 15 mL), dried (Na2SC>4) and concentrated under reduced pressure. TheAttorney Ref. No. 01234-0009-00PCTresidue was purified by column chromatography (SiO2, 100% PE to 1:1:0.2 PE / EtOAc / DCM) to give the title compound as a yellow solid (230 mg, 83%). LCMS m / z = 311 [M+H]+.

[0235] Step 5. Synthesis of 2-chloro-7-((lS,2R)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0236] To a solution of 3-(2-chloro-4-(((lS,2R)-2-fluorocyclopentyl)amino)pyrimidin-5-yl)-N, N-dimethylpropiolamide (230 mg, 740 pmol) in DMSO (4 mL) was added cesium carbonate (482 mg, 1.48 mmol) and the mixture stirred at 30 °C for 60 h. The reaction mixture was quenched with water (10 mL) at 25 °C and extracted with EtOAc (3x 10 mL). The combined organics were washed with brine (2x 10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE) to give the title compound as a yellow solid (140 mg, 60%). LCMS m / z = 311 [M+H]+.

[0237] Intermediate 16. (lR,2R)-2-fluorocyclopentan-l-amine hydrochloride.BocHN' H2NFF

[0238] To a solution of tert-butyl ((lR,2R)-2-fluorocyclopentyl)carbamate (700 mg, 3.44 mmol) in DCM (2 mL) was added HCl / dioxane (2 M, 2 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (480 mg, crude) which was used without purification. LCMS m / z = 104 [M+H]+.

[0239] Intermediate 17. (lS,2S)-2-fluorocyclopentan-l-amine hydrochloride.BocHN' H2NFi..Fi..

[0240] The title compound was prepared as a yellow solid (480 mg, crude) from tert-butyl ((lS,2S)-2-fluorocyclopentyl)carbamate using an analogous method to that described for Intermediate 16. LCMS m / z = 104 [M+H]+.

[0241] Intermediate 18. (rac)-(lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropan-l-amine.Attorney Ref. No. 01234-0009-00PCT

[0242] Step 1. Synthesis of (Z)-2-(2-((tert-butyldimethylsilyl)oxy)vinyl)isoindoline-l, 3-dione.

[0243] The title compound was prepared by pumping Solutions 1 and 2 together in a flow reactor (flow reactor coil 3.175 mm, 30 mL, 20 °C).

[0244] Solution 1 was prepared from 2-(l,3-dioxoisoindolin-2-yl)acetaldehyde (22.0 g, 116 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (61.5 g, 233 mmol) in THF (440 mL). Solution 2 was prepared from lithium bis(trimethylsilyl)amide (1 M, 174 mL).

[0245] The solution 1 was pumped at a flow rate of 75.356 mL / min and solution 2 at a flow rate of 24.644 mL / min into the flow reactor with a residence time of 0.3 min and the reaction mixture was collected after running 0.3 mins.

[0246] The reaction mixture was added to saturated ammonium chloride solution at 0 °C and extracted with EtOAc (3x 150 mL). The combined organics were washed with brine (2x 50 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-10% EtOAc / PE) to give the title compound as a yellow oil (17.0 g, 48%). 'HNMR (400MHz, CDC13) 8: 7.87 (dd, 2H), 7.72 (dd, 2H), 6.51 (d, 1H), 5.42 (d, 1H), 0.87 (s, 9H), 0.17 (s, 6H).

[0247] Step 2. Synthesis of (rac)-2-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)-cyclopropyl)isoindoline-l, 3-dione.

[0248] To a solution of (Z)-2-(2-((tert-butyldimethylsilyl)oxy)vinyl)isoindoline-l,3-dione (Step 1, 5.00 g, 16.5 mmol) in toluene (50 mL) was added ZnEt2 (1 M, 82.4 mL) and CH2I2 (82.4 mmol, 6.65 mL) at 0 °C and the mixture stirred at 60 °C for 16 h. The mixture was added to saturated ammonium chloride solution at 0°C under nitrogen and extracted with ethyl acetate (3x 150 mL). The combined organics were washed with brine (2x 50 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-10% EtOAc / PE) to give the title compound as a yellow solid (3.50 g, 67%). 'HNMR (400MHz, CDCI3) 6: 7.81 (dd,, 2H), 7.70 (dd, 2H), 3.95-3.89 (m, 1H), 3.84-2.78 (m, 1H), 1.32-1.28 (m, 1H), 1.24-1.19 (m, 1H), 0.93 (s, 8H), 0.22 (d, 6H).

[0249] Step 3. Synthesis of (rac)-(lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropan-1 -amine.Attorney Ref. No. 01234-0009-00PCT

[0250] To a solution of (rac)-2-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)-cyclopropyl)isoindoline-l, 3-dione (3.50 g, 11.0 mmol) in DCM (40 mL) and ethanol (8 mL) was added NH2NH2. H2O (176 mmol, 8.56 mL) and the mixture stirred at 25 °C for 4 h. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure to give the title compound as a yellow solid (2.00 g, crude).1H NMR (400MHz, CDCl3) δ: 3.22-3.18 (m, 1H), 2.38-2.33 (m, 1H), 0.87 (s, 9H), 0.72-0.66 (m, 1H), 0.58-0.52 (m, 1H), 0.08 (d, 6H).

[0251] Intermediates 19-36

[0252] The title compounds were prepared from 2,4-dichloro-5-iodopyrimidine, the appropriate amine (RNH2) and N, N-dimethylpropiolamide (Intermediate 1), but N-methylprop-2-ynamide was used in Intermediate 26, using an analogous 3-Step method as described for Intermediate 2.Intermediate Name / Structure / Amine / Data19 2-chloro-N, N,7-trimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide J ^1-Amine: methanamine hydrochloride; LCMS m / z = 239 [M+H]+.20 2-chloro-N, N-dimethyl-7-(oxetan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6- carb oxami dec'vNA VXXM,Amine: oxetan-3 -amine; LCMS m / z = 281 [M+H]+.21 7-(bicyclo[2.1. l]hexan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide / Amine: bicyclo[2.1.1]hexan-2-amine; LCMS m / z = 305 [M+H]+.22 (rac)-7-((lS,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamideAttorney Ref. No. 01234-0009-00PCT / Amine: (rac)-(lS,2R,4R)-bicyclo[2.2.1]heptan-2-amine; LCMS m / z = 319 [M+H]+.2-chloro-7-((lR,2R)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamideF" CclvV o / Amine: (lR,2R)-2-fluorocyclopentan-l-amine, intermediate 16; LCMS m / z = 311 [M+H]+.2-chloro-7-((lS,2S)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide / Amine: (lS,2S)-2-fluorocyclopentan-l -amine, intermediate 17; LCMS m / z = 311 [M+H]+.7-(bicyclo[3.3.1]nonan-9-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamideCL N id o / Amine: bicyclo[3.3.1]nonan-9-amine; LCMS m / z = 347 [M+H]+.2-chloro-7-isopropyl-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6- carb oxami deAttorney Ref. No. 01234-0009-00PCTHN- XXM >Amine: isopropylamine; 'H NMR (400MHZ, MeOH-cU): 8.87 (s, 1H), 6.95 (s, 1H), 5.35 (td, 1H), 2.93 (s, 3H), 1.69 (d, 6H).(S)-2-chloro-7-(l-hydroxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamideOH CL N N O / Amine: (S)-2-aminopropan-l-ol; 'HNMR (400 MHz, DMSO-de) 6: 8.96 (s, 1H), 6.78 (s, 1H), 5.11-4.69 (m, 1H), 4.61-4.48 (m, 1H), 4.04-3.95 (m, 1H), 3.69 (dd, 1H), 3.03 (d, 6H), 1.54 (d, 3H).(R)-2-chloro-N, N-dimethyl-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamidec°Amine: (R)-tetrahydrofuran-3 -amine; LCMS m / z = 295 [M+H]+.(S)-2-chloro-N, N-dimethyl-7-(tetrahydrofuran-3-yl)-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide.pAmine: (S)-tetrahydrofuran-3 -amine; 'H NMR (400 MHz, DMSO-de) 6: 8.98 (s, 1H), 6.85 (s, 1H), 5.15 (dd, 1H), 4.23-4.12 (m, 1H), 4.05-3.93 (m, 2H), 3.87 (dt, 1H), 3.04 (d, 6H), 2.56 (d, 1H), 2.39-2.28 (m, 1H).2-chloro-7-(l,3-difluoropropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamideAttorney Ref. No. 01234-0009-00PCTF CL N M O / Amine: l,3-difluoropropan-2-amine; LCMS m / z = 303 [M+H]+.(S)-2-chloro-7-(l-fluoropropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideF CL N M oXXH- / Amine: (S)-l-fluoropropan-2-amine; LCMS m / z = 285 [M+H]+.(rac)-7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro- N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide p^OTBSclvVAmine: (rac)-(lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropan-l-amine, intermediate 18; LCMS m / z = 395 [M+H]+.2-chloro-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d] pyrimidine-6-carb oxami deCI^N^N \l- XXM,Amine: cyclopropylamine; LCMS m / z = 265 [M+H]+.2-chloro-7-cyclobutyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carb oxami deCI-. A,7 O / Amine: cyclobutylamine; LCMS m / z = 279 [M+H]+.7-(tert-butyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carb oxami deAttorney Ref. No. 01234-0009-00PCT / Amine: tert-butylamine; 'HNMR (400 MHz, DMSO-d6) 8.93 (s, 1H), 6.67 (s, 1H), 3.01 (s, 3H), 2.96 (s, 3H), 1.74 (s, 9H).36 7-(sec-butyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carb oxami deCL N K] oXX? V / Amine: sec-butylamine; LCMS m / z = 281 [M+H]+.

[0253] Intermediate 37. (R)-2-chloro-7-(l-fluoropropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Step 2Step 3

[0254] Step 1. Synthesis of (R)-2-chloro-N-(l-fluoropropan-2-yl)-5-iodopyrimidin-4-amine.

[0255] To a solution of 2,4-dichloro-5-iodopyrimidine (1.00 g, 3.64 mmol) and (R)-l-fluoropropan-2-amine hydrochloride (454 mg, 7.28 mmol) in MeCN (10 mL) was added DIPEA (1.2 g, 9.10 mmol) and the mixture stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (60 mL) and extracted with EtOAc (3x 60 mL). The combined organics were washed with brine (3x 60 mL), dried QSfeSCh) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 0-50%% EtOAc / PE) to give the title compound as a yellow solid (830 mg, 67%). LCMS m / z = 316 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0256] Step 2. Synthesis of (R)-3-(2-chloro-4-((l-fluoropropan-2-yl)amino)pyrimidin-5-yl)-N, N-dimethylpropiolamide.

[0257] A mixture of (R)-2-chloro-N-(l-fluoropropan-2-yl)-5-iodopyrimidin-4-amine (Step 1, 830 mg, 2.63 mmol), N, N-dimethylpropiolamide (Intermediate 1, 383 mg, 3.95 mmol), Cui (50.1 mg, 263 pmol), DIPEA (6.77 mmol, 1.18 mL) and Pd(PPh3)2C12 (92.3 mg, 131 pmol) in DMF (8 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 80 °C for 2 h. The residue mixture was diluted with water (60 mL) and extracted with EtOAc (3x 60 mL). The combined organics were washed with brine (3x 60 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (0.1% formic acid condition) to give the title compound as a yellow solid (420 mg, 51%). LCMS m / z = 285 [M+H]+.

[0258] Step 3. Synthesis of (R)-2-chloro-7-(l-fluoropropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0259] To a solution of (R)-3-(2-chloro-4-((l-fluoropropan-2-yl)amino)pyrimidin-5-yl)-N, N-dimethylpropiolamide (Step 3, 370 mg, 1.30 mmol) in DMSO (4 mL) was added CS2CO3 (847 g, 2.60 mmol) and the mixture stirred at 25 °C for 24 h. The mixture was filtered and the filtrate evaporated to dryness under reduced pressure. The residue was purified by reversephase chromatography (0.1% FA condition) to give the title compound as a yellow solid (80 mg, 20%). LCMS m / z = 285 [M+H]+.

[0260] Intermediate 38. (R)-2-chloro-7-(l-methoxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0261] To a solution of (R)-2-chloro-7-(l-hydroxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 3, 200 mg, 707 pmol) in THF (2 mL) was degassed and purged with nitrogen (x3). Methyl iodide (1.06 mmol, 66 pL) was added and the mixture stirred at 0 °C for 30 min followed by NaH (42.4 mg, 1.06 mmol, 60% purity) and the resulting mixture stirred at 0 °C for 1 h under nitrogen. The reaction was quenched by water (5 mL) and extracted with EtOAc (3x 10 mL). The combined organics were washed with brine (10 mL x 3), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO2, 50% EtOAc / PE) to give the title compound as a white solid (100 mg, 47%).Attorney Ref. No. 01234-0009-00PCT'H NMR (400MHz, DMSO-d6) 6: 8.97 (s, 1H), 6.82 (s, 1H), 4.90-4.76 (m, 1H), 3.96 (t, 1H), 3.61 (dd, 1H), 3.14 (s, 3H), 3.04 (d, 6H), 1.54 (d, 3H).

[0262] Intermediate 39. (S)-2-chloro-7-(l-methoxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0263] The title compound was prepared as a yellow oil (120 mg, 57%) from (S)-2-chloro-7-(l-hydroxypropan-2-yl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 27) using an analogous method to that described for Intermediate 38. 'H NMR (400MHz, CDC13) 8: 8.80 (s, 1H), 6.51 (s, 1H), 4.91-4.79 (m, 1H), 4.17 (t, 1H), 3.60 (dd, 1H), 3.22 (s, 3H), 3.16 (s, 3H), 3.10 (s, 3H), 1.69 (s, 3H).

[0264] Intermediate 40 and 41. 7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)-cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide and 7-((lS,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.TBSCT TBSCf TBSCf

[0265] (rac)-7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 32) was purified by SFC (DAICEL CHIRALPAK IC, 250 x 30 mm, 10 mm); 60% IPA (0.1% NH4OH) in CO2) to afford:

[0266] Peak 1, Intermediate 40: 7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((l S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (yellow oil; 700 mg, 29%);

[0267] Peak 2: Intermediate 41: 7-((lS,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (yellow oil; 700 mg, 29%);Attorney Ref. No. 01234-0009-00PCT

[0268] Intermediate 42. 2-chloro-7-((lR,2R)-2-methoxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 2-chloro-7-((l S,2S)-2-methoxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.TBSCf HCf MeCf

[0269] Step 1. Synthesis of 2-chloro-7-((lR,2R)-2-hydroxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 2-chloro-7-((l S,2S)-2-hydroxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0270] To a solution of 7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((l S,2S)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 40, 300 mg, 760 pmol) in dioxane (3 mL) was added HC1 (1 M, 3 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was diluted with saturated aqueous sodium bicarbonate solution to pH=8~9, diluted with water (30 mL) and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SC>4) and evaporated to dryness. The residue was purified by column chromatography (SiC>2, 0-100% EtOAc / PE) to give a title compound as an off-white solid (150 mg, 70%).NMR (400MHz, DMSO-d6) 8: 8.93 (s, 1H), 6.77 (s, 1H), 5.79 (d, 1H), 3.71-3.64 (m, 1H), 3.33-3.29 (m, 1H), 3.06 (s, 3H), 3.00 (s, 3H), 1.23-1.16 (m, 1H), 1.16-1.09 (m, 1H).

[0271] Step 2. Synthesis of 2-chloro-7-((lR,2R)-2-methoxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 2-chloro-7-((l S,2S)-2-methoxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0272] To a solution of 2-chloro-7-((lR,2R)- 2-hydroxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 2-chloro-7-((l S,2S)-2-hydroxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Step 1, 70.0 mg, 249 pmol) in DMF (2 mL) was added methyl iodide (354 mg, 2.49 mmol) and NaH (15.0 mg, 374 pmol, 60% purity) and the mixture stirred at 0 °C for 2 h. The mixture was diluted with saturated ammonium chloride solution to 0 °C and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE) to give the title compound (60.0 mg, 82%). LCMS m / z = 295 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0273] Intermediate 43. 2-chloro-7-((lS,2S)-2-methoxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 2-chloro-7-((lR,2R)-2-methoxycyclopropyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.TBSCf HO'' MeO'

[0274] The title compound was prepared from 7-((lS,2S)-2-((tert-butyldimethylsilyl)-oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2R)-2-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 41) using an analogous 2-step method as described for Intermediate 42. LCMS m / z = 295 [M+H]+.

[0275] Intermediate 44. (rac)-3-(4-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3 -y l)-3 -methyl-2-oxo-2, 3 -dihydro- lH-benzo[d]imidazol- 1 -yl)piperidine-2, 6-dione.Boc BocAttorney Ref. No. 01234-0009-00PCT

[0276] Step 1. Synthesis of tert-butyl 9-(3-fluoro-2-ni trophenyl)-3, 9-diazaspiro[5.5]undecane-3-carboxylate.

[0277] To a solution of tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (26.4 g, 104 mmol) in dimethylsulfoxide (140 mL) and DIPEA (26.8 g, 207 mmol) was added 1,3-difluoro-2-nitrobenzene (15.0 g, 94.3 mmol) and the mixture stirred at 25 °C for 1 h. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2x 700 mL). The combined organics were washed with brine (80 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 0-25% EtOAc / PE) to afford the title compound as a yellow solid (35.0 g, 94%).XH NMR (400MHz, CDC13): 7.34 (dt, 1H), 6.92 (d, 1H), 6.83 (t, 1H), 3.42-3.36 (m, 4H), 3.05-2.99 (m, 4H), 1.63-1.59 (m, 4H), 1.48 (s, 4H), 1.47 (s, 9H).

[0278] Step 2. Synthesis of tert-butyl 9-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0279] LiHMDS (1 mol / L, 163 mL) was added dropwise to a solution of 2,6-bis(benzyloxy)pyridin-3-amine (24.9 g, 81.3 mmol) in THF (200 mL) at -78 °C and the mixture stirred at -78 °C for 1 h. Tert-butyl 9-(3-fluoro-2-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 2, 32.0 g, 81.3 mmol) in THF (100 mL) was added dropwise at -78 °C and the mixture stirred at 0 °C for 2 h. The reaction mixture was quenched by addition sat aq NH4OH (1000 mL) at 0 °C and extracted with EtOAc (3x 500 mL). The combined organics were washed with brine (100 mL), dried (Na2SO4), concentrated under reduced pressure and theAttorney Ref. No. 01234-0009-00PCTresidue purified by column chromatography (SiCh, 0-33% EtOAc / PE) to give the title compound as a red solid (54.0 g, 89%). LCMS m / z = 680 [M+H]+.

[0280] Step 3. Synthesis of tert-butyl 9-(2-amino-3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0281] To a solution of tert-butyl 9-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-nitrophenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 2, 54.0 g, 79.4 mmol) in THF (250 mL) was stirred at 25 °C until becoming clear solution. The solution was hydrogenated in a flow reactor over a fixed bed of granular catalyst Pt / C (10.0 g, 476 pmol, 1% purity) and heated to 60 °C. The hydrogen back pressure regulator was adjusted to 0.1 Mpa and the above solution was pumped into the fixed bed with a flow rate of 1.0 mL / min and a hydrogen flow rate of 20 mL / min. The reaction was continued for 7 h. The reaction mixture was filtered and concentrated under reduced pressure to give the title compound as a brown oil (55.4 g, crude). 'HNMR (400MHz, CDC13): 7.47-7.42 (m, 4H), 7.40-7.30 (m, 6H), 6.95 (d, 1H), 6.83 (dd, 2H), 6.73-6.66 (m, 1H), 6.29 (d, 1H), 5.44 (s, 2H), 5.30 (s, 2H), 5.28 (s, 1H), 4.06 (s, 2H), 3.46-3.41 (m, 4H), 2.89 (s, 4H), 1.67 (s, 4H), 1.54 (s, 4H), 1.48 (s, 9H).

[0282] Step 4. Synthesis of tert-butyl 9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxo-2,3-dihydro- lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3 -carboxylate.

[0283] To a solution of tert-butyl 9-(2-amino-3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 1.10 g, 1.69 mmol) in MeCN (10 mL) was added CDI (686 mg, 4.23 mmol) and the mixture stirred at 80 °C for 12 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 0-25% EtOAc / PE) to afford the title compound as a yellow solid (720 mg, 58%). LCMS m / z = 676 [M+H]+.

[0284] Step 5. Synthesis of tert-butyl 9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0285] To a solution of tert-butyl 9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 4; 14.8 g, 21.9 mmol) in anhydrous THF (150 mL) was added sodium hydride (1.75 g, 43.8 mmol) at 0 °C and the mixture stirred at 0 °C for 0.5 h. Methyl iodide (4.66 g, 32.8 mmol) was added and the mixture stirred at 25 °C for 4 h under nitrogen. The reaction was quenched with water (400 mL) and extracted with EtOAc (3x 300 mL). The combined organics were dried (Na2SO4), concentrated under reduced pressure and the residue purified by column chromatography (SiO2,Attorney Ref. No. 01234-0009-00PCT0-66% EtOAc / PE) to give the title compound as a yellow oil (10.9 g, 72%). LCMS m / z = 690 [M+H]+.

[0286] Step 6. Synthesis of tert-butyl (rac)-9-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0287] The following reaction was carried out under flow conditions as described below.

[0288] Solution SI: A solution of tert-butyl (rac)-9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 5, 10.9 g, 15.8 mmol) in dioxane (300 mL) and IPA (300 mL) was prepared.

[0289] Fixed Bed, FLR1 95 mL volume): The fixed bed was packed with granular catalyst 5% Pd(OH)2 (44.3 g, 15.8 mmol, 5% purity) and heated to 80°C. The H2 back pressure regulator was adjusted to 2.5 MPa.

[0290] Solution SI was pumped into the fixed bed, FLR1 at 80 C at a flow rate of 0.3 mL / min and the reaction mixture collected after a 24 h run time. The collected sample was evaporated to dryness to afford the title compound as a white solid (9 g, crude). LCMS m / z = 512 [M+H]+.

[0291] Step 7. Synthesis of (rac)-3-(3-methyl-2-oxo-4-(3,9-diazaspiro[5.5]undecan-3-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione trifluoroacetate.

[0292] To a solution of tert-butyl (rac)-9-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo- 2.3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 6, 3.00 g, 5.86 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (9.21 g, 80.7 mmol) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated to give the title compound as a black solid (3.10 g, crude). LCMS m / z = 319 [M+H]+.

[0293] Step 8. Synthesis of (rac)-3-(3-methyl-4-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2,6-dione.

[0294] To a solution of (rac)-3-(3-methyl-2-oxo-4-(3,9-diazaspiro[5.5]undecan-3-yl)- 2.3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 7, 3.10 g, 5.90 mmol) in DMF (30 mL) was added triethylamine (2.39 g, 23.6 mmol) and 5-fluoro-2-nitropyridine (1.68 g, 11.8 mmol) and the reaction mixture stirred at 30 °C for 2 h. The mixture was diluted with water (100 mL) and the crude product was triturated with petroleum ether at 20°C for 20 min. The mixture was filtered and the filter was concentrated to give the title compound as a yellow oil (2.90 g, 92%). LCMS m / z = 534 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0295] Step 9. Synthesis of (rac)-3-(4-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3 -y l)-3 -methyl-2-oxo-2, 3 -dihydro- lH-benzo[d]imidazol- 1 -yl)piperidine-2, 6-dione.

[0296] To a solution of (rac)-3-(3-methyl-4-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 8, 2.90 g, 5.44 mmol) in anhydrous THF (100 mL) was added Platino-vanadium carbon (435 mg, 1.67 mmol) and the mixture stirred at 25 °C for 2 h under hydrogen atmosphere (15 Psi). The reaction mixture was concentrated to give the title compound as a black solid (3.00 g, crude). LCMS m / z = 504 [M+H]+.

[0297] Intermediate 45. (rac)-3-(6-(7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0298] Step 1. Synthesis of tert-butyl (rac)-2-(2-(2, 6-dioxopiperi din-3 -yl)-3-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate.

[0299] A mixture of 3-(6-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (2.00 g, 6.19 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (2.80 g, 12.4 mmol), Ir(ppy)2(dtbbpy)PFe (113 mg, 124 pmol), dibrom onickel-l,2-dimethoxy ethane (95.5 mg, 309 pmol) and DABCO (1.25 g, 11.1 mmol, 1.23 mL) in DMA (40 mL) was degassed and purged with argon and the reaction mixture stirred at 25 °C for 16 h irradiated with a 455 nm blue LED. The reaction mixture was acidified to pH 3 with formic acid, diluted with acetonitrile (150 mL) and the solids collected by filtration to afford the title compound as a green solid (1.80 g, 62%). LCMS m / z = 469 [M+H]+.

[0300] Step 2. Synthesis of (rac)-3-(l-oxo-6-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine-2, 6-dione trifluoroacetate.Attorney Ref. No. 01234-0009-00PCT

[0301] To a solution of tert-butyl (rac)-2-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (Step 1, 200 mg, 427 pmol) in dichloromethane (8 mL) was added trifluoroacetic acid (13.5 mmol, 1 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (205 mg, 100% yield). LCMS m / z = 369 [M+H]+.

[0302] Step 3. Synthesis of (rac)-3-(6-(7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0303] To a solution of (rac)-3-(l-oxo-6-(2,7-diazaspiro[3.5]nonan-2-yl)isoindolin-2-yl)piperidine-2, 6-dione trifluoroacetate (205 mg, 425 pmol) in DMF (2 mL) was added DIPEA (275 mg, 2.12 mmol) and 5-fluoro-2-nitropyridine (78.5 mg, 552 pmol) and the mixture stirred at 25 °C for 16 h. The reaction mixture was poured into water (100 mL) with stirring and the solids collected by filtration. The filter cake was dried under reduced pressure and the residue triturated with water (2 mL) at 25 °C for 30 minutes to afford the title compound as a yellow solid (120 mg, 58%). LCMS m / z = 491 [M+H]+.

[0304] Step 4. Synthesis of (rac)-3-(6-(7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione.

[0305] To a solution of (rac)-3-(6-(7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (Step 3, 120 mg, 245 pmol) in DMF (10 mL) was added Pd / C (52.1 mg, 48.9 pmol, 10% purity) under nitrogen. The suspension was degassed under reduced pressure and purged with hydrogen several times and the reaction mixture stirred under hydrogen (15 psi) at 25 °C for 16 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound as a grey solid (140 mg, crude). LCMS m / z = 461 [M+H]+.

[0306] Intermediate 46. l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate.

[0307] To a solution of 3 -hydroxy- l-(4-methoxybenzyl)piperidine-2, 6-dione (8.00 g, 32.0 mmol) and Py (64.1 mmol, 5.18 mL) in DCM (80 mL) was added dropwise TfzO (48.1 mmol, 7.94 mL) at 0 °C and the mixture stirred at 0-10 °C for 1 h under N2. The reaction mixture was diluted with water (200 mL) and extracted with DCM (3x 200 mL). The combined organics were washed with brine (3x 200 mL), dried (ISfeSCh), concentrated under reducedAttorney Ref. No. 01234-0009-00PCTpressure and the residue was purified by column chromatography (SiCh, 15-25% EtOAc / PE) to give the title compound as a white solid (9.50 g, 77%). LCMS m / z = 382 [M+H]+.

[0308] Intermediate 47. (rac)-3 -(4'-bromo-2'-oxospiro[cyclopropane- 1,3 '-indolin]- 1 yl)piperidine-2, 6-dione.Step 2

[0309] Step 1. Synthesis of 4'-bromospiro[cyclopropane-l,3'-indolin]-2'-one.

[0310] To solution of 4-bromoindolin-2-one (3.71 g, 17.5 mmol) in DMF (90 mL) was added (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (9.30 g, 21.0 mmol) at 25 °C, and the mixture stirred at 25 °C for 5 min. TEA (5.31 g, 52.4 mmol) was added and the mixture stirred at 25 °C for 4 h. On completion, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2x 100 mL). The combined organics were washed with brine (4x 200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, 0-20% EtOAc / PE) followed by reversed phase chromatography (0.1% TFA condition) to afford the title compound as a yellow solid (2.60 g, 62%). LCMS m / z = 238 [M+H]+.

[0311] Step 2. Synthesis of (rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0312] To a solution of 4'-bromospiro[cyclopropane-l,3'-indolin]-2'-one (Step 1, 2.00 g, 8.40 mmol) in THF (100 mL) was added KO'Bu (1 M in THF, 10.1 mL) at 0 °C and the mixture stirred at 25 °C for 1 h. l-(4-methoxybenzyl)-2,6-dioxopiperi din-3 -yl trifluoromethanesulfonate (Intermediate 46, 4.00 g, 10.5 mmol) was added at 0 °C and the mixture stirred at 25 °C for 2 h. On completion, the reaction mixture was quenched by addition water (100 mL) and extracted with EtOAc (2x 100 mL). The combined organics were washed with brine (2x 200 mL), dried (Na? SO4) and concentrated under reduced pressure. The residue was purified by reversed phase chromatography (0.1% TFA condition) to afford the title compound as a yellow solid (3.00 g, 76%). LCMS m / z = 471 [M+H]+.

[0313] Step 3. Synthesis of (rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0314] To a solution of 3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-T-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione (Step 2, 2.10 g, 4.47 mmol) in TFA (20 mL) was added trifluoromethanesulfonic acid (2.0 mL) at 25 °C and the mixture stirred at 60 °C for 6 h. On completion, the reaction mixture was concentrated under reduced pressure and the residue purified by reverse phase chromatography (0.1% TFA condition) to afford the title compound as a yellow solid (750 mg, 48%). LCMS m / z = 349 [M+H]+.

[0315] Intermediate 48. (rac)-3-(4'-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3 -yl)-2'-oxospiro[cyclopropane- 1,3 '-indolin]- 1 '-yl)piperidine-2, 6-dione.

[0316] Step 1. Synthesis of tert-butyl (rac)-9-(l'-(2,6-dioxopiperidin-3-yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-4'-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0317] A mixture of (rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione (Intermediate 47, 500 mg, 1.43 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (437 mg, 1.72 mmol), Ruphos Pd G2 (178 mg, 229 pmol), RuPhos (134 mg, 286 pmol)and 4A MS (100 mg) in toluene (15 mL) was degassed and purged with nitrogen (x3). LiHMDS (1 M, 7.16 mL) was added to the mixture at 25°C and the reaction mixture stirred at 90°C for 2 h under nitrogen. The reaction mixture was quenched by the addition of formic acid (1 mL) at 25 °C, concentrated under reduced pressure and the residue dissolved in DMSO. The mixture was purified by reverse phase chromatography (60%Attorney Ref. No. 01234-0009-00PCTMeCN / FLO (0.1% HCO2H)) to give the title compound as a yellow solid (120 mg, 12%).LCMS m / z = 523 [M+H]+.

[0318] Step 2. Synthesis of 3-(2'-oxo-4'-(3,9-diazaspiro[5.5]undecan-3-yl)spiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione trifluoroacetate.

[0319] To a solution of tert-butyl 9-(l'-(2,6-dioxopiperi din-3 -yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-4'-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 235 mg, 450 pmol) in DCM (5 mL) was added TFA (1 mL) and the reaction mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a brown oil (240 mg, crude). LCMS m / z = 423 [M+H]+.

[0320] Step 3. Synthesis of 3-(4'-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2'-oxospiro[cyclopropane- 1,3 '-indolin]- 1 '-yl)piperidine-2, 6-dione.

[0321] To a solution of 3-(2'-oxo-4'-(3,9-diazaspiro[5.5]undecan-3-yl)spiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione trifluoroacetate (Step 2, 240 mg, 447 pmol) in DMF (4 mL) was added TEA (1.34 mmol, 187 pL) and 5-fluoro-2-nitropyridine (95.4 mg, 671 pmol) and the mixture stirred at 25 °C for 16 h. The reaction mixture was acidified with formic acid and evaporated to dryness under reduced pressure. The residue was triturated with DMF / water (1:2) at 25 °C for 15 min to give the title compound as a yellow solid (200 mg, 81%). LCMS m / z = 545 [M+H]+.

[0322] Step 4. Synthesis of 3-(4'-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione.

[0323] To a solution of 3-(4'-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2'-oxospiro[cy cl opropane- 1,3 '-indolin]- l'-yl)piperidine-2, 6-dione (Step 3, 195 mg, 358 pmol) in DMF (4 mL) was added Pt / V / C (100 mg, 383 pmol) under nitrogen. The suspension was degassed and purged with hydrogen (x3) and stirred under hydrogen (15 Psi) at 28 °C for 16 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a black solid (184 mg, crude). LCMS m / z = 515 [M+H]+.

[0324] Intermediate 49. (rac)-3-(4-(3-(4-(6-aminopyri din-3 -yl)piperazin-l-yl)azeti din- 1-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0325] Step 1. Synthesis of tert-butyl (rac)-4-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)azetidin-3-yl)piperazine-l-carboxylate.

[0326] To a solution of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (1.12 g, 3.31 mmol) in dioxane (10 mL) was added tert-butyl 4-(azetidin-3-yl)piperazine-l -carboxylate (0.80 g, 3.31 mmol), Pd-PEPPSI-IheptCl (322 mg, 331 pmol), cesium carbonate (3.24 g, 9.94 mmol) and 4A MS (200 mg) and the reaction mixture stirred at 110 °C for 16 h under nitrogen. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3x 20 mL). The combined organics were evaporated under reduced pressure and the residue purified by prep-HPLC-7 (28-58% MeCN) to give the title compound as a yellow solid (590 mg, 33%). LCMS m / z = 499 [M+H]+.

[0327] Step 2, 3, 4. Synthesis of (rac)-3-(4-(3-(4-(6-aminopyri din-3 -yl)piperazin-l-yl)azetidin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0328] The title compound was prepared from tert-butyl (rac)-4-(l-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)azetidin-3-yl)piperazine-l -carboxylate (Step 1) using an analogous 3-Step method as described for Intermediate 48, Step 2,3,4. LCMS m / z = 491 [M+H]+.

[0329] Intermediate 50. (rac)-3-(4'-(3-(4-(6-aminopyri din-3 -yl)piperazin-l-yl)azetidin-l-yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0330] Step 1. Synthesis oftert-butyl (rac)-4-(l-(l'-(2,6-dioxopiperidin-3-yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-4'-yl)azetidin-3-yl)piperazine-l-carboxylate.

[0331] A mixture of (rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione (Intermediate 47, 1.50 g, 4.30 mmol), tert-butyl 4-(azeti din-3 -yl)piperazine-l -carboxylate (1.24 g, 5.15 mmol), Pd-PEPPSI-IHeptCl (418 mg, 430 pmol), cesium carbonate (2.80 g, 8.59 mmol) and 4A MS (200 mg) in dioxane (35 mL) was degassed and purged with nitrogen (x3) and then stirred at 100 °C for 2 h under nitrogen. The reaction mixture was acidified with formic acid, concentrated under reduced pressure and the residue dissolved in DMSO and purified by reverse phase chromatography (22% MeCN / FLO (0.1% HCO2H)) to give the title compound as a white solid (1.00 g, 36%). LCMS m / z = 510 [M+H]+.

[0332] Step 2. Synthesis of 3-(2'-oxo-4'-(3-(piperazin-l-yl)azetidin-l-yl)spiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione trifluoroacetate.

[0333] To a solution of tert-butyl 4-(l-(l'-(2,6-dioxopiperidin-3-yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-4'-yl)azetidin-3-yl)piperazine-l-carboxylate (Step 1, 500 mg, 981 pmol) in DCM (10 mL) was added TFA (2 mL) and the mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a brown oil (520 mg, crude). LCMS m / z = 410 [M+H]+.

[0334] Step 3. Synthesis of 3-(4'-(3-(4-(6-nitropyridin-3-yl)piperazin-l-yl)azetidin-l-yl)-2'-oxospiro[cyclopropane- 1,3 '-indolin]- 1 '-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0335] To a solution of 3 -(2'-oxo-4'-(3 -(piperazin- l-yl)azeti din- l-yl)spiro[cy cl opropane- 1, 3'-indolin]-l'-yl)piperidine-2, 6-dione trifluoroacetate (Step 2, 510 mg, 974 pmol) and 5-fluoro-2-nitropyridine (208 mg, 1.46 mmol) in DMF (8 mL) was added TEA (2.92 mmol, 407 pL) and the mixture stirred at 25 °C for 16 h. The reaction mixture was acidified with formic acid, concentrated under reduced pressure and the residue triturated with DMF / H2O (1:2) at 25 °C for 15 minutes to give the title compound as a yellow solid (355 mg, 68%). LCMS m / z = 532 [M+H]+.

[0336] Step 4. Synthesis of 3-(4'-(3-(4-(6-aminopyridin-3-yl)piperazin-l-yl)azetidin-l-yl)-2'-oxospiro[cyclopropane- 1,3 '-indolin]- 1 '-yl)piperidine-2, 6-dione.

[0337] To a solution of 3-(4'-(3-(4-(6-nitropyridin-3-yl)piperazin-l-yl)azetidin-l-yl)-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione (Step 3, 355 mg, 668 pmol) in DMSO (6 mL) was added Pt / V / C (180 mg, 690 pmol) under nitrogen. The suspension was degassed and purged with hydrogen (x3) and the mixture stirred under hydrogen (15 Psi) at 28 °C for 16 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a yellow solid (334 mg, 99%). LCMS m / z = 502 [M+H]+.

[0338] Intermediate 51. (rac)-3-(2'-oxo-4'-(2,7-diazaspiro[3.5]nonan-2-yl)spiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione trifluoroacetate.

[0339] The title compound was prepared from (rac)-3-(4'-bromo-2'-oxospiro[cyclopropane-l,3'-indolin]-l'-yl)piperidine-2, 6-dione (Intermediate 47) and tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate using an analogous 2-Step method to that described for Intermediate 50, Step 1 and 2. LCMS m / z = 395 [M+H]+.

[0340] Intermediate 52. (rac)-3-(4-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-3,3-dimethyl-2-oxoindolin-l-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0341] Step 1. Synthesis of tert-butyl (rac)-9-(2-oxoindolin-4-yl)-3, 9-diazaspiro[5.5]undecane-3-carboxylate.

[0342] A mixture of 4-bromoindolin-2-one (3.00 g, 14.15 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (2.88 g, 11.3 mmol), Pd-PEPPSI-IheptCl (688 mg, 707 pmol), cesium carbonate (9.22 g, 28.3 mmol) in dioxane (60 mL) was degassed and purged with nitrogen (x3) and the mixture stirred at 100 °C for 3 h under nitrogen. The reaction mixture was diluted with EtOAc (150 mL) and the solids removed by filtration. The filtrate diluted with water (100 mL) and extracted with EtOAc (300 mL) (5x 60 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO2, 0-66% EtOAc / PE) to give the title compound as a yellow solid (800 mg, 15%).XH NMR (400MHz, DMSO-de) 8: 10.24 (s, 1H), 7.07 (t, 1H), 6.54 (d, 1H), 6.43 (d, 1H), 3.38 (s, 6H), 2.96 (s, 4H), 1.55 (s, 4H), 1.39 (s, 13H).

[0343] Step 2. Synthesis of tert-butyl (rac)-9-(3,3-dimethyl-2-oxoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0344] To a solution of tert-butyl (rac)-9-(2-oxoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 600 mg, 1.56 mmol) in THF (15 mL) was addedAttorney Ref. No. 01234-0009-00PCTLiHMDS (1 M, 6.23 mL) at -78°C under nitrogen and the reaction mixture was stirred at -78 °C for 0.5 h. Mel (3.27 mmol, 204 pL) was added at -78 °C and the mixture stirred at 20 °C for 2 h. The reaction mixture was cooled to 0 °C and diluted with saturated ammonium chloride solution and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine (2x 30 mL), dried (Na2SO4) and evaporated to dryness. The residue was purified by column chromatography (SiCh, 0-66% EtOAc / PE) to give the title compound as a yellow solid (400 mg, 62%). 'HNMR (400MHz, DMSO-d6) 8: 10.27 (s, 1H), 7.20-7.08 (m, 1H), 7.01 (d, 1H), 6.66 (d, 1H), 3.32 (s, 4H), 2.74 (s, 4H), 1.57 (s, 4H), 1.46 (s, 4H), 1.40 (s, 9H), 1.34 (s, 6H).

[0345] Step 3. Synthesis of tert-butyl (rac)-9-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carb oxy late.

[0346] To a solution of tert-butyl (rac)-9-(3,3-dimethyl-2-oxoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 2, 510 mg, 1.23 mmol) and l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (Intermediate 46, 940 mg, 2.47 mmol) in THF (10 mL) was added potassium tert-butoxide (1 M, 2.47 mL) at 0°C and the mixture stirred at 0 °C for 2 h. The reaction mixture was added to saturated ammonium chloride solution at 0 °C and extracted with EtOAc (3x 30 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (0.1% FA condition) to give the title compound as a yellow solid (260 mg, 31%). LCMS m / z = 645 [M+H]+.

[0347] Step 4. Synthesis of (rac)-3-(3,3-dimethyl-2-oxo-4-(3,9-diazaspiro[5.5]undecan-3 -yl)indolin-l-yl)piperidine-2, 6-dione.

[0348] To a solution of tert-butyl (rac)-9-(l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 260 mg, 403 pmol) in TFA (5 mL) was added TfOH (0.5 mL) and the mixture stirred at 60 °C for 8 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reversed-phase chromatography (0.1% TFA condition) to give the title compound as a yellow oil (150 mg, 69%). LCMS m / z = 425 [M+H]+.

[0349] Step 5. Synthesis of (rac)-3-(3,3-dimethyl-4-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3 -yl)-2-oxoindolin- 1 -yl)piperidine-2, 6-dione.

[0350] To a solution of (rac)-3-(3,3-dimethyl-2-oxo-4-(3,9-diazaspiro[5.5]undecan-3-yl)indolin-l-yl)piperidine-2, 6-dione (Step 4, 150 mg, 319 pmol) in DMSO (4 mL) was added TEA (96.8 mg, 956 pmol) and 5-fluoro-2-nitropyridine (67.9 mg, 478 pmol) and the mixture stirred at 30 °C for 16 h. The reaction mixture was purified by reversed-phase chromatographyAttorney Ref. No. 01234-0009-00PCT(0.1% TFA condition) to afford the title compound as a yellow solid (130 mg, 62%). LCMS m / z = 547 [M+H]+.

[0351] Step 6. Synthesis of (rac)-3-(4-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-3,3-dimethyl-2-oxoindolin-l-yl)piperidine-2, 6-dione.

[0352] A mixture of (rac)-3-(3,3-dimethyl-4-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxoindolin-l-yl)piperidine-2, 6-dione (Step 5, 130 mg, 197 pmol) in DMF (5 mL) was added Pt / V / C (53.8 mg, 206 pmol) under nitrogen and degassed and purged with nitrogen (x3). The reaction mixture was purged with hydrogen (x3) and stirred at 30 °C for 16 h under hydrogen. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound as a black solid (160 mg, crude) which was used without further purification. LCMS m / z = 517 [M+H]+.

[0353] Intermediate 53. (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)piperidine-2, 6-dione.

[0354] Step 1. Synthesis of 4-bromo-3,3-dimethylindolin-2-one.

[0355] To a solution of 4-bromoindolin-2-one (2.00 g, 9.43 mmol) in THF (30 mL) was degassed and purged with nitrogen and cooled to -78°C. To this was added LiHMDS (1 M, 28.3 mL) and the mixture stirred at -78°C for 0.5 hour and Mel (23.5 mmol, 1.47 mL) was added and the mixture stirred at 25 °C for 2 h. The reaction mixture was quenched by the addition of NH4CI solution (100 mL) at 25 °C and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine (3x 100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 10-25% EtOAc / PE) to give the title compound as a white solid (1.30 g, 57%). LCMS m / z = 240 [M+H]+.

[0356] Step 2. Synthesis of (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0357] Potassium tert-butoxide (1 M, 7.50 mL) was added to a solution of 4-bromo-3,3-dimethylindolin-2-one (Step 1, 1.20 g, 5.00 mmol) and 1 -(4-m ethoxyb enzyl)-2, 6-di oxopiperi din-3 -yl trifluoromethanesulfonate (Intermediate 46, 2.86 g, 7.50 mmol) in THF (20 mL) at 0 °C and the mixture stirred at 25 °C for 2 h. The reaction mixture was quenched by addition NH4CI solution (50 mL) at 25 °C and extracted with EtOAc (3x 50 mL). The combined organics were washed with brine (3x 50 mL), dried (Na2SO4) and concentrated under reducedAttorney Ref. No. 01234-0009-00PCTpressure. The residue was purified by column chromatography (SiCh, 15-50% EtOAc / PE) to give the title compound as a white solid (1.15 g, 48%). 'H NMR. (400MHz, DMSO-de): 7.24-7.18 (m, 3H), 7.17-7.10 (m, 1H), 7.02-6.76 (m, 3H), 5.49-5.36 (m, 1H), 4.88-4.71 (m, 2H), 3.72 (s, 3H), 3.02 (d, 1H), 2.79 (dd, 1H), 2.65 (dd, 1H), 2.06-1.95 (m, 1H), 1.44 (s, 6H).

[0358] Step 3. Synthesis of (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)piperidine-2, 6-dione.

[0359] To a solution of (rac)-3-(4-bromo-3,3-dimethyl-2-oxoindolin-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione (Step 2, 300 mg, 636 pmol) in TFA (2 mL) was added TfOH (2.26 mmol, 0.2 mL) and the mixture stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced and the residue purified by reversed-phase chromatography (0.1% FA) to give the title compound as a white solid (120 mg, 34%).XH NMR (400MHz, DMSO-de): 11.10 (s, 1H), 7.28-7.17 (m, 2H), 7.06 (s, 1H), 5.35-5.20 (m, 1H), 2.93-2.79 (m, 1H), 2.72-2.55 (m, 2H), 1.99 (d, 1H), 1.43 (d, 6H).

[0360] Intermediate 54. 2-((5-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide trifluoroacetate.Boc

[0361] Step 1. Synthesis of tert-butyl 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate.

[0362] To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.00 g, 4.42 mmol) and 5-chloro-2-nitropyridine (771 mg, 4.86 mmol) in MeCN (15 mL) was added potassium carbonate (916 mg, 6.63 mmol) and the mixture stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (3x 50 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 65% EtOAc / PE) to give the title compound as a yellow solid (540 mg, 36%). LCMS m / z = 349 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0363] Step 2. Synthesis of tert-butyl 7-(6-aminopyridin-3-yl)-2,7-di azaspiro [3.5 ] nonane-2-carb oxy 1 ate.

[0364] To a solution of tert-butyl 7-(6-nitropyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 1, 540 mg, 1.55 mmol) in EtOH (3.5 mL) and water (1.5 mL) was added ammonium chloride (829 mg, 15.5 mmol) at 20 °C. The mixture was warmed to 80 °C and iron (433 mg, 7.75 mmol) added portion wise and the reaction mixture stirred at 80 °C for 2 h. The solids were removed by filtration and the filtrate concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with brine (3x 50 mL), dried (ISfeSCh), concentrated under reduced pressure and the residue purified by column chromatography (SiCh, 5% MeOH / EtOAc) to give the title compound as a green oil (390 mg, 78%). LCMS m / z = 319 [M+H]+.

[0365] Step 3. Synthesis of tert-butyl 7-(6-((7-cyclopropyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate.

[0366] A mixture of tert-butyl 7-(6-aminopyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 2, 200 mg, 628 pmol), 2-chloro-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 4, 166 mg, 628 pmol), BrettPhos Pd G4) (57.8 mg, 62.8 pmol), Brettphos (67.4 mg, 125 pmol) and potassium acetate (184 mg, 1.88 mmol) in dioxane (2 mL) was degassed and purged with nitrogen (x3) and the mixture stirred at 100 °C for 2 h under nitrogen. The residue was diluted with water (60 mL) and extracted with ethyl acetate (3x 60 mL). The combined organics were washed with brine (3x 60 mL), dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (10: 1 DCM / MeOH) to give the title compound as a white solid (300 mg, 87%). LCMS m / z = 547 [M+H]+.

[0367] Step 4. Synthesis of 2-((5-(2,7-diazaspiro[3.5]nonan-7-yl)pyridin-2-yl)amino)-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide trifluoroacetate.

[0368] To a solution of tert-butyl 7-(6-((7-cyclopropyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 3, 300 mg, 548 pmol) in DCM (1.5 mL) was added trifluoroacetic acid (1.5 mL) and the mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a white solid (170 mg, 55%) which was used without further purification. LCMS m / z = 447 [M+H]+.

[0369] Intermediate 55. 2-((5-(4-(azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Attorney Ref. No. 01234-0009-00PCT

[0370] Step 1. Synthesis of tert-butyl 3-(4-(6-nitropyridin-3-yl)piperazin-l-yl)azetidine-1 -carboxylate.

[0371] To a solution of tert-butyl 3 -(piperazin- l-yl)azetidine-l -carboxylate (2.40 g, 9.94 mmol) and DIPEA (2.57 g, 19.9 mmol) in MeCN (25 mL) was added 5-fluoro-2-nitropyridine (1.41 g, 9.94 mmol) and the reaction mixture stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography (ISCO®; 80 g Sepa Flash®, 0-100% EtOAc / DCM) to afford the title compound as a yellow solid (3.40 g, 94%). LCMS m / z = 364 [M+H]+.

[0372] Step 2. Synthesis of tert-butyl 3-(4-(6-aminopyridin-3-yl)piperazin-l-yl)azetidine- 1 -carboxylate.

[0373] To a solution of tert-butyl 3 -(4-(6-nitropyri din-3 -yl)piperazin-l -yl)azeti dine- 1-carboxylate (Step 1, 3.40 g, 9.36 mmol) in MeOH (30 mL) and THF (10 mL) was added Pt / V / C (0.34 g, 1.30 mmol) under nitrogen. The reaction mixture was degassed under vacuum, purged with hydrogen several times and stirred under hydrogen (15 Psi) at 25 °C for 5 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound as a brown solid (3.10 g, 99%) which was used without further purification. LCMS m / z = 334 [M+H]+.

[0374] Step 3. Synthesis of tert-butyl 3-(4-(6-((7-cyclopropyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidine-l-carboxylate.

[0375] A mixture of tert-butyl 3 -(4-(6-aminopyri din-3 -yl)piperazin-l -yl)azeti dine- 1-carboxylate (Step 2, 252 mg, 755 pmol), 2-chloro-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 4, 200 mg, 755 pmol), BrettPhos Pd G4 (70.0 mg, 76.0 pmol), Brettphos (82.0 mg, 152 pmol) and potassium acetate (222 mg, 2.27 mmol) in dioxane (4 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 100 °C for 2 h under nitrogen. The reaction mixture was concentrated under reduced pressure the residue purified by reverse-phase chromatography (0.1% TFA condition). The residue wasAttorney Ref. No. 01234-0009-00PCTfurther purified by silica gel chromatography (ISCO®; 12 g Sepa Flash®; 0-10% DCM / MeOH) to afford the title compound as a yellow solid (360 mg, 82%). LCMS m / z = 562 [M+H]+.

[0376] Step 4. Synthesis of 2-((5-(4-(azetidin-3-yl)piperazin-l-yl)pyridin-2-yl)amino)-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0377] To a solution of tert-butyl 3-(4-(6-((7-cyclopropyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazin-l-yl)azetidine-l-carboxylate (Step 3, 360 mg, 641 pmol) in DCM (10 mL) was added TFA (3.07 g, 26.9 mmol) and the reaction mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue treated with alkaline resin to obtain the title compound as a yellow solid (200 mg, 64%) which was used without further purification. LCMS m / z = 462 [M+H]+.

[0378] Intermediate 56. [(R)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione] or [(R)-3-(l-oxo-4-((R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione],Attomey Ref. No. 01234-0009-00PCT

[0379] Step 1. Synthesis of benzyl (S)-4-(l -(tert-butoxy carbonyl)azeti din-2-yl)piperidine-l -carboxylate or benzyl (R)-4-(l-(tert-butoxycarbonyl)azetidin-2-yl)piperidine-l-carb oxy late.

[0380] A mixture of l-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (6.75 g, 33.5 mmol), benzyl 4-bromopiperidine-l -carboxylate (5.00 g, 16.7 mmol), Ir(ppy)2(dtbpy)(PFe) (376 mg, 335 pmol), (DME)NiC12 (368 mg, 1.68 mmol), 4-methoxy-2-(4-methoxy-2-pyridyl)pyridine (362 mg, 1.68 mmol), potassium carbonate (9.27 g, 67.0 mmol), and water (6.04 g, 335 mmol) in acetonitrile (50 mL) and EtOAc (50 mL) was degassed and purged with nitrogen. The reaction mixture was stirred at 25 °C for 16 h irradiated with a 455nm blue LED. The reaction mixture was quenched by addition of water (30 mL) and extracted with EtOAc (600 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated under reduced pressure. The crude material was purified by column chromatography (SiO2, 0-100% EtOAc / PE) to afford a yellow oil (2.50 g, 31%). This was further purified by chiral-SFC (Diacel Chiralpak IG, 250 x 50 mm, 10 mm; 35% IPA (0.1% NH4OH) in CO2) to afford the title compound as the first eluting isomer as a yellow solid (0.7 g, 65%). LCMS m / z = 375 [M+H]+.

[0381] Step 2. Synthesis of benzyl (S)-4-(azetidin-2-yl)piperidine-l -carboxylate or benzyl (R)-4-(azetidin-2-yl)piperidine-l -carboxylate.

[0382] To a solution of benzyl (S)-4-(l-(tert-butoxycarbonyl)azetidin-2-yl)piperidine-l-carboxylate or benzyl (R)-4-(l -(tert-butoxy carbonyl)azeti din-2 -yl)piperi dine- 1 -carboxylate (Step 1, 0.85 g, 2.27 mmol) in DCM (7.5 mL) was added TFA (2.45 g, 21.4 mmol). The mixture was stirred at 25 °C for 2 h. The crude product was purified by reverse-phase (0.1% FA condition) to give the title compound (0.70 g, 96%) as yellow oil. LCMS m / z = 275 [M+H]+.

[0383] Step 3. Synthesis of (benzyl 4-((S)-l-(2-((R)-2,6-dioxopiperi din-3 -yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l -carboxylate and benzyl 4-((S)-l-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l-carboxylate) or (benzyl 4-Attorney Ref. No. 01234-0009-00PCT((R)-l-(2-((R)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l-carboxylate and benzyl 4-((R)-l-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine- 1 -carboxylate).

[0384] A mixture of benzyl (S)-4-(azeti din-2 -yl)piperi dine- 1 -carboxylate or benzyl (R)-4-(azetidin-2-yl)piperidine-l -carboxylate (Step 2, 0.50 g, 1.56 mmol), 3-(4-bromo-l-oxoisoindolin-2-yl)piperidine-2, 6-dione (504 mg, 1.56 mmol), Brettphos Pd G4 (151 mg, 156 pmol), Brettphos (100.3 mg, 156 pmol) and cesium carbonate (1.02 g, 3.12 mmol) in 1,4-di oxane (8 mL) was stirred at 100 °C for 2 h. The reaction mixture was quenched with citric acid and the pH adjusted to 5-6 and extracted with DCM (150 mL). The combined organic layers were washed with brine (30 mL), dried (ISfeSCh), and concentrated under reduced pressure. The crude material was purified by column chromatography (SiC>2, 0-100% EtOAc / DCM) to give the title compound as a brown solid (0.25 g, 22%). LCMS m / z = 517 [M+H]+.

[0385] Step 4. Synthesis of [(R)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((S)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione] or [(R)-3-(l-oxo-4-((R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione and (S)-3-(l-oxo-4-((R)-2-(piperidin-4-yl)azetidin-l-yl)isoindolin-2-yl)piperidine-2, 6-dione],

[0386] To a solution of [(benzyl 4-((S)-l-(2-((R)-2,6-dioxopiperi din-3 -yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l -carboxylate and benzyl 4-((S)-l-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l-carboxylate)] or [(benzyl 4-((R)- 1 -(2-((R)-2,6-dioxopiperi din-3 -y 1)- 1 -oxoisoindolin-4-yl)azeti din-2 -yl)piperi dine- 1 -carboxylate and benzyl 4-((R)-l-(2-((S)-2,6-dioxopiperidin-3-yl)-l-oxoisoindolin-4-yl)azetidin-2-yl)piperidine-l -carboxylate)] (Step 1, 0.22 g, 425 pmol) in DMF (5 mL) was added Pd(OH)2 (44.0 mg, 156 pmol) and Pd / C (45.3 mg, 42.5 pmol) and the mixture stirred at 25 °C for 2 h under a hydrogen atmosphere. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a white solid (0.15 g, crude). LCMS m / z = 383 [M+H]+.

[0387] Intermediate 57. (rac)-3-(7-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3 -y 1)- 1 -methyl- lH-indazol-3 -yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCTSteP7HN~A n A \ Ar \ / \s JiNINH2

[0388] Step 1. Synthesis of 7-bromo-3-iodo-l-methyl-lH-indazole.

[0389] To a solution of 7-bromo-3-iodo-lH-indazole (5.00 g, 15.5 mmol) in DMF (50 mL) was added cesium carbonate (15.1 g, 46.5 mmol) and iodomethane (2.42 g, 17.0 mmol) and the reaction mixture stirred at 25 °C for 2 h. The reaction mixture was diluted with H2O (300 ml) and extracted with ethyl acetate (3x 100 ml). The combined organics were dried (ISfeSCh), evaporated to dryness under pressure reduced and the residue purified by column chromatography (SiC>2, 0-10% EtOAc / PE) to afford the title compound as a white solid (4.00 g, 76%). 'HNMR (400 MHz, DMSO-d6): 7.71 (d, 1H), 7.44 (d, 1H), 7.11 (t, 1H), 4.33 (s, 3H).

[0390] Step 2. Synthesis of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-l-methyl-lH-indazole.

[0391] Amixture of 7-bromo-3-iodo-l-methyl-lH-indazole (Step 1, 3.80 g, 11.3 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (4.94 g, 11.8 mmol), cesium carbonate (7.35 g, 22.6 mmol), Pd(dppf)C12 (825 mg, 1.13 mmol) in THF (50 mL) and water (10 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 85 °C for 12 h under nitrogen. The mixture was poured onto water (200 mL) and extracted with EtOAc (2x 100 mL x 2). The combined organics were concentrated under reduced pressure andAttorney Ref. No. 01234-0009-00PCTthe residue purified by column chromatography (SiO2, 0-10% EtOAc / PE) to afford the title compound as a white solid (3.00 g, 37%). LCMS m / z = 500 [M+H]+.

[0392] Step 3. Synthesis of tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-7-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0393] A mixture of 3-(2,6-bis(benzyloxy)pyridin-3-yl)-7-bromo-l-methyl-lH-indazole (Step 2, 1.35 g, 2.70 mmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (824 mg, 3.24 mmol), Pd2(dba)s (247 mg, 270 pmol), RuPhos (252mg, 540 pmol) and sodium tert-butoxide (778 mg, 8.09 mmol) in dioxane (30 mL) was degassed and purged with nitrogen (x3) and the reaction mixture was stirred at 100 °C for 2 h under nitrogen. The reaction mixture was poured into water (200 mL) then extracted with EtOAc (2x 50 mL). The combined organics were concentrated under reduced pressure and the residue purified by column chromatography (SiCh, 10-25% EtOAc / PE) to give the title compound as a yellow solid (1.30 g, 61%). LCMS m / z = 674 [M+H]+.

[0394] Step 4. Synthesis of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0395] To a solution of palladium on carbon (200 mg, 10% purity) and palladium hydroxide on carbon (200 mg, 20% purity) in anhydrous tetrahydrofuran (10 mL) was added tert-butyl 9-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-l-methyl-lH-indazol-7-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 3, 1.30 g, 1.93 mmol) in anhydrous tetrahydrofuran (20 mL) under nitrogen. The suspension was degassed and purged with hydrogen (x3) and stirred under hydrogen (50 Psi) at 30 °C for 16 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a brown solid (700 mg, crude). 'HNMR (400 MHz, DMSO-d6) 8: 10.88 (s, 1H), 7.37 (d, 1H), 7.09-6.94 (m, 2H), 4.35-4.30 (m, 1H), 4.24 (s, 3H), 3.10-2.77 (m, 5H), 2.73-2.58 (m, 3H), 2.36-2.28 (m, 1H), 2.21-2.12 (m, 1H), 1.83-1.72 (s, 2H), 1.65-1.52 (m, 4H), 1.45-1.32 (m, 13H).

[0396] Step 5. Synthesis of (rac)-3-(l-methyl-7-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2, 6-dione trifluoroacetate.

[0397] To a solution of tert-butyl 9-(3-(2,6-dioxopiperidin-3-yl)-l-methyl-lH-indazol-7-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 4, 700 mg, 1.41 mmol) in TFA (1 mL) and DCM (5 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (700 mg, 87%). LCMS m / z = 396 [M+H]+.

[0398] Step 6. Synthesis of (rac)-3-(l-methyl-7-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0399] To a solution of (rac)-3-(l-methyl-7-(3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2, 6-dione trifluoroacetate (Step 5, 700 mg, 1.37 mmol) and 5-fluoro-2-nitro-pyridine (254 mg, 1.79 mmol) in DMSO (7 mL) was added DIPEA (888 mg, 6.87 mmol) and the mixture stirred at 40 °C for 1 h. Formic acid was added to the mixture until pH=6 and evaporated to dryness under reduced pressure. The residue was triturated with water (50 ml) at 25 °C for 30 mins to give the title compound as a green solid (700 mg, 78%). LCMS m / z = 518 [M+H]+.

[0400] Step 7: Synthesis of (rac)-3-(7-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3 -yl)- 1 -methyl- lH-indazol-3 -yl)piperidine-2, 6-dione.

[0401] To a solution of Pt / V / C (900 mg, 69 pmol, 2% purity) in THF (10 mL) was added (rac)-3-(l-methyl-7-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-lH-indazol-3-yl)piperidine-2, 6-dione, (Step 6, 470 mg, 908 pmol) in DMF (20 mL) under nitrogen. The suspension was degassed and purged with hydrogen (x3) and the mixture stirred under hydrogen (15 Psi.) at 25 °C for 2h. The reaction mixture was filtered to remove Pt / V / C and the filtrate concentrated under reduced pressure to give the title compound as a brown solid (254 mg, crude) which was used without further purification. LCMS m / z = 488 [M+H]+.

[0402] Intermediate 58. (rac)-3 -(4-(4-( 1 -(6-aminopyri din-3 -yl)azeti din-3 -yl)piperazin- 1 -yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0403] Step 1. Synthesis of tert-butyl (rac)-3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)piperazin-l-yl)azetidine-l-carboxylate.

[0404] To a solution of (rac)-3-(4-bromo-3-methyl-2-oxo-benzimidazol-l-yl)piperidine-2, 6-dione (500 mg, 1.48 mmol), tert-butyl 3-piperazin-l-ylazetidine-l-carboxylate (392 mg,Attorney Ref. No. 01234-0009-00PCT1.63 mmol), RuPhos Pd G2 (114 mg, 147 μmol) and RuPhos (103 mg, 221 μmol) in toluene (10 mL) was added LiHMDS (1 M, 7.39 mL) and the mixture stirred at 90 °C for 2 h. The reaction was quenched by the addition of formic acid (30 mL) and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (0.1% formic acid condition) to give the title compound as a yellow solid (370 mg, 47%). LCMS m / z = 499 [M+H]+.

[0405] Step 2. Synthesis of (rac)-3-(4-(4-(azeti din-3 -yl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0406] To a solution of tert-butyl (rac)-3-(4-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)piperazin-l-yl)azetidine-l-carboxylate (Step 2, 350 mg, 702 μmol) in DCM (3 mL) was added TFA (460 mg, 4.04 mmol) and the mixture was stirred at 25 °C for 1 h. The reaction mixture was evaporated to dryness to give the title compound as a yellow oil (350 mg, crude). LCMS m / z = 399 [M+H]+.

[0407] Step 3. Synthesis of (rac)-3 -(3 -methyl-4-(4-(l-(6-nitropyri din-3 -yl)azeti din-3 -yl)piperazin-l-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0408] A solution of (rac)-3-(4-(4-(azetidin-3-yl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 2, 350 mg, 682 μmol), 5-fluoro-2-nitro-pyridine, (145 mg, 1.02 mmol) and TEA (207 mg, 2.05 mmol) in DMSO (3 mL) and the mixture stirred at 25 °C for 16 h. The reaction mixture was evaporated to dryness and the residue purified by reverse-phase HPLC (0.1% formic acid condition) to give the title compound as a yellow oil (150 mg, 41%). LCMS m / z = 521 [M+H]+.

[0409] Step 4. Synthesis of (rac)-3-(4-(4-(l-(6-aminopyridin-3-yl)azetidin-3-yl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0410] To a solution of (rac)-3-(3-methyl-4-(4-(l-(6-nitropyridin-3-yl)azetidin-3-yl)piperazin-l-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 3, 100 mg, 192 μmol) in DMF (2 mL) was added Pt / V / C (167 mg, 19.2 μmol) and the mixture stirred at 25 °C for 2 h under hydrogen. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a brown oil (90.0 mg, crude). LCMS m / z = 491 [M+H]+.

[0411] Intermediate 59. (rac)-3-(4-(4-(((ls,3s)-3-((6-aminopyridin-3-yl)oxy)cyclobutyl)methyl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0412] Step 1. Synthesis of methyl (Is, 3s)-3-((6-nitropyridin-3-yl)oxy)cyclobutane-l-carboxylate.

[0413] To a solution of methyl (lr,3r)-3-hydroxycyclobutane-l-carboxylate (1.70 g, 13.1 mmol) in THF (30 mL) was added dropwise NaH (784 mg, 19.6 mmol, 60% purity) at 0 °C and the mixture stirred for 15 min. 5-fluoro-2-nitro-pyridine (1.86 g, 13.1 mmol) was added dropwise at 0 °C and the reaction mixture stirred at 0 °C for 15 min. The reaction was quenched by addition saturated ammonium chloride solution (400 mL) at 0 °C and extracted with EtOAc (3x 200 mL). The combined organics were washed with brine (3x 500 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 80 g Septa Flash®; 0-30% EtOAc / PE) followed by reverse-phase chromatography (0.1% formic acid condition) to give the title compound as a yellow solid (1.10 g, 33 %). LCMS m / z = 253 [M+H]+.

[0414] Step 2. Synthesis of ((ls,3s)-3-((6-nitropyridin-3-yl)oxy)cyclobutyl)methanol.

[0415] A solution of methyl (lr,3r)-3-((6-nitropyridin-3-yl)oxy)cyclobutane-l-carboxylate (Step 1, 1.04 g, 4.14 mmol) in THF (40 mL) was degassed and purged with nitrogen (x3) and LAH (2.5 M, 3.3 mL) was added at 0 °C and the mixture stirred at 0 °C for 1 h under nitrogen. The reaction was quenched with H2O (0.3 mL), 15% aq. NaOH (0.3 mL) and H2O (0.9 mL). The mixture was diluted with methanol (200 mL) and dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO®; 20 g Septa Flash; 0-50% EtOAc / PE) to give the title compound as a yellow solid (144 mg, 16 %). LCMS m / z = 225 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0416] Step 3. Synthesis of (ls,3s)-3-((6-nitropyridin-3-yl)oxy)cyclobutane-l-carbaldehyde.

[0417] To a solution of ((lr,3r)-3-((6-nitropyridin-3-yl)oxy)cyclobutyl)methanol (Step 2, 144 mg, 642 μmol) in DMSO (1.5 mL) was added 2-Iodoxybenzoic acid (IBX) (270 mg, 963 pmol) and the mixture stirred at 25 °C for 4 h. The reaction mixture was filtered and the filtrate evaporated to give the title compound as a yellow liquid (142 mg, 100 %). LCMS m / z = 223 [M+H]+.

[0418] Step 4. Synthesis of (rac)-3-(3-methyl-4-(4-(((ls,3s)-3-((6-nitropyridin-3-yl)oxy)cyclobutyl)methyl)piperazin-l-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0419] To a solution of (rac)-3-(3-methyl-2-oxo-4-piperazin-l-yl-benzimidazol-l-yl)piperidine-2, 6-dione, (292 mg, 639 μmol, TFA salt) in DCM (3 mL) and DMSO (0.5 mL) was added TEA (323 mg, 3.20 mmol) and AcOH (192 mg, 3.20 mmol) and the reaction mixture stirred at 25 °C for 10 min. (lr,3r)-3-[(6-nitro-3-pyridyl)oxy] cyclobutanecarbaldehyde (Step 3, 142 mg, 639 μmol) was added and the reaction mixture stirred at -30 °C for 10 min. STAB (406 mg, 1.92 mmol) was added stitting continued at -30 °C for 2 h. The reaction mixture was quenched by addition water (1 mL) and concentrated under reduced pressure. The residue was purified by reversed-phase (0.1% formic acid condition) to give the title compound as a yellow solid (210 mg, 60 %). LCMS m / z = 550 [M+H]+.

[0420] Step 5. Synthesis of(rac)-3-(4-(4-(((ls,3s)-3-((6-aminopyridin-3-yl)oxy)cyclobutyl)methyl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.

[0421] To a solution of (rac)-3-(3-methyl-4-(4-(((ls,3s)-3-((6-nitropyridin-3-yl)oxy)cyclobutyl)methyl)piperazin-l-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione (Step 4, 210 mg, 382 μmol) in DMF (3 mL) was added Pt / V / C (21.0 mg, 80.4 μmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times and stirred under hydrogen (15 psi) at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a black solid (198 mg, 100 %). LCMS m / z = 520 [M+H]+.

[0422] Intermediate 60. (rac)-3-(4-(4-(((lr,3r)-3-((6-aminopyridin-3-yl)oxy)cyclobutyl)methyl)piperazin-l-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0423] The title compound was prepared from methyl (lr,3r)-3-hydroxycyclobutane-l-carboxylate and 5-fluoro-2-nitro-pyridine using an analogous 5-Step procedure as described for Intermediate 59. LCMS m / z = 520 [M+H]+.

[0424] Intermediate 61. (rac)-3-(4-(9-(6-aminopyridin-3-yl)-8-oxo-3,9-diazaspiro[5.5]undecan-3 -y l)-3 -methyl-2-oxo-2, 3 -dihydro- lH-benzo[d]imidazol- 1 -yl)piperidine-2, 6-dione.BocillAttorney Ref. No. 01234-0009-00PCT

[0425] Step 1. Synthesis of tert-butyl 9-(6-chloropyridin-3-yl)-8-oxo-3, 9-diazaspiro[5.5]undecane-3-carboxylate.

[0426] A mixture of tert-butyl 8-oxo-3,9-diazaspiro[5.5]undecane-3-carboxylate (500 mg, 1.86 mmol), 5-bromo-2-chloropyridine (359 mg, 1.86 mmol), Pd2(dba)s (171 mg, 186 μmol), XantPhos (216 mg, 372.65 μmol) and CsCCh (1.82 g, 5.59 mmol) in dioxane (10 mL) was degassed and purged with nitrogen (x3) and the mixture stirred at 80 °C for 4 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by column chromatography (SiCh, 10-100% EtOAc / PE) to give the title compound as a yellow solid (2.40 g, 76%). LCMS m / z = 380 [M+H]+.

[0427] Step 2. Synthesis of 3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one trifluoroacetate.

[0428] To a solution of tert-butyl 9-(6-chloropyridin-3-yl)-8-oxo-3, 9-diazaspiro [5.5] undecane-3 -carboxylate (Step 1, 2.20 g, 5.79 mmol) in DCM (30 mL) was added TFA (10 mL) and the mixture stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow solid (2.30 g, crude). LCMS m / z = 280 [M+H]+.

[0429] Step 3. Synthesis of 3-(6-chloropyridin-3-yl)-9-(3-fluoro-2-nitrophenyl)-3,9-diazaspiro[5.5]undecan-2-one.Attorney Ref. No. 01234-0009-00PCT

[0430] To a solution of 3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one trifluoroacetate (2.30 g, 5.84 mmol) in DMSO (30 mL) was added DIPEA (3.77 g, 29.2 mmol, 5.09 mL) and l,3-difluoro-2-nitrobenzene (1.86 g, 11.7 mmol) and the reaction mixture stirred at 40 °C for 4 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (ISfeSCh), concentrated under reduced pressure and the residue purified by column chromatography (SiO2, 10-100% EtOAc / PE) to give the title compound as a yellow solid (2.40 g, 78%). LCMS m / z = 419 [M+H]+.

[0431] Step 4. Synthesis of 9-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-nitrophenyl)-3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one.

[0432] Lithium bis(trimethylsilyl)amide (1 M, 11.3 mL) was added to a solution of 2,6-bis(benzyloxy)pyridin-3-amine (2.50 g, 8.17 mmol) in THF (40 mL) at -78 °C and the mixture stirred at -78 °C for 1 h under nitrogen. 3-(6-chloropyridin-3-yl)-9-(3-fluoro-2-nitrophenyl)-3,9-diazaspiro[5.5]undecan-2-one (Step 3, 1.90 g, 4.54 mmol) was added at -78°C and the mixture stirred at 25 °C for 12 h under nitrogen. The mixture was quenched with ammonium chloride (100 mL) at -20 °C and extracted with ethyl acetate (3x 100 mL). The combined organics were dried (Na2SC>4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 10-100% EtOAc / PE) to give the title compound as a yellow solid (2.00 g, 59%). LCMS m / z = 705 [M+H]+.

[0433] Step 5. Synthesis of 9-(2-amino-3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)-3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one.

[0434] To a solution of 9-(3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)-2-nitrophenyl)-3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one (Step 4, 2.00 g, 2.84 mmol) in anhydrous THF (50 mL) was added Pt / V / C (800 mg, 2.84 mmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen and then stirred under hydrogen (15 psi) at 25 °C for 3 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 10-100% EtOAc / PE) to give the title compound as a yellow solid (1.50 g, 74%). LCMS m / z = 675 [M+H]+.

[0435] Step 6. 9-(l-(2, 6-bis (benzyloxy) pyridin-3-yl)-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-3-(6-chloropyri din-3 -yl)-3, 9-diazaspiro [5.5] undecan-2-one

[0436] To a solution of 9-(2-amino-3-((2,6-bis(benzyloxy)pyridin-3-yl)amino)phenyl)-3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one (Step 5, 1.50 g, 2.22 mmol) in MeCN (40 mL) was added CDI (1.08 g, 6.66 mmol) and the mixture stirred at 80 °C for 4 h. The reaction mixture was concentrated under reduced pressure and the residue triturated with 25%Attorney Ref. No. 01234-0009-00PCTEtOAc / PE at 25 °C for 30 min to give the title compound as a yellow solid (1.50 g, 96%).LCMS m / z = 701 [M+H]+.

[0437] Step 7. Synthesis of 9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one.

[0438] To a solution of 9-(l-(2, 6-bis (benzyloxy) pyri din-3 -yl)-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-3-(6-chloropyridin-3-yl)-3, 9-diazaspiro [5.5] undecan-2-one (Step 6, 1.40 g, 2.00 mmol) in anhydrous THF (30 mL) was added NaH (280 mg, 7.00 mmol, 60% purity) at 0 °C and the mixture stirred at 0 °C for 0.5 h. To this was added iodomethane (426 mg, 3.00 mmol) the mixture stirred at 25 °C for 12 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organics were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiC>2, 10-100% EtOAc / PE) to give the title compound as a yellow solid (1.00 g, 66%). LCMS m / z = 715 [M+H]+.

[0439] Step 8. Synthesis of tert-butyl (5-(9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-2-oxo-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)carbamate.

[0440] A mixture of 9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3-(6-chloropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-2-one (Step 7, 500 mg, 699 μmol), tert-butyl carbamate (164 mg, 1.40 mmol), BrettPhos (75.1 mg, 140 μmol), BrettPhos Pd G4 (64.4 mg, 69.9 μmol) and cesium carbonate (456 mg, 1.40 mmol) in dioxane (10 mL) was degassed and purged with nitrogen (x3) and the mixture stirred at 100 °C for 3 h under nitrogen. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by prep-HPLC-5 (65-95% MeCN) to give the title compound as a white solid (240 mg, 39%). LCMS m / z = 796 [M+H]+.

[0441] Step 9. Synthesis of tert-butyl (5-(9-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-2-oxo-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)carbamate.

[0442] To a solution tert-butyl (5-(9-(l-(2,6-bis(benzyloxy)pyridin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-2-oxo-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)carbamate (Step 8, 220 mg, 276 μmol) in anhydrous THF (15 mL) and DMF (15 mL) was added acetic acid (16.6 mg, 276 μmol), Pd / C (100 mg, 94.0 μmol, 10% purity) and Pd(OH)2 (100 mg, 142 μmol, 20% purity) under nitrogen. The suspension was degassed and purged with hydrogen (x3). The reaction mixture was stirred under hydrogen (25 Psi) at 25 °C for 16 h. The reaction mixture was filtered, concentrated under reduced pressure and the residue purified byAttorney Ref. No. 01234-0009-00PCTprep-HPLC-5 (40-60% MeCN) to give the title compound as a red solid (40.0 mg, 23%). LCMS m / z = 618 [M+H]+.

[0443] Step 10. Synthesis of (rac)-3-(4-(9-(6-aminopyridin-3-yl)-8-oxo-3,9-diazaspiro[5.5]undecan-3 -y l)-3 -methyl-2-oxo-2, 3 -dihydro- lH-benzo[d]imidazol- 1 -yl)piperidine-2, 6-dione.

[0444] To a solution of tert-butyl (rac)-(5-(9-(l-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2, 3-dihydro-lH-benzo[d]imidazol-4-yl)-2-oxo-3,9-diazaspiro[5.5]undecan-3-yl)pyridin-2-yl)carbamate (Step 9, 35.0 mg, 56.7 μmol) in DCM (1.5 mL) was added TFA (0.5 mL) and the mixture stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure and the residue purified by prep-HPLC-1 (3-33% MeCN) to give the title compound as a yellow solid (25.0 mg, 85%). LCMS m / z = 518 [M+H]+.

[0445] Intermediate 62. (rac)-3-(4-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0446] Step 1. Synthesis of (rac)-3-(4-bromo-6-fhioro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0447] Potassium tert-butoxide (1.83 g, 16.3 mmol) was added dropwise to a solution of 7-bromo-5-fhioro-l-methyl-l,3-dihydro-2H-benzo[d]imidazol-2-one (2.00 g, 8.16 mmol) in anhydrous THF (40 mL) at 0 °C and the mixture stirred at 0 °C for 0.5 h. l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl trifluoromethanesulfonate (Intermediate 46, 4.67 g, 12.2 mmol) wasAttorney Ref. No. 01234-0009-00PCTadded dropwise at 0 °C and the resulting mixture stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reverse-phase chromatography (0.1% formic acid condition) to give the title compound as a yellow solid (1.70 g, 42.4%). LCMS m / z = 478 [M+H]+.

[0448] Step 2. Synthesis of tert-butyl (rac)-9-(6-fluoro- l-(l-(4-m ethoxyb enzyl)-2, 6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0449] A mixture of (rac)-3-(4-bromo-6-fluoro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione (Step 1, 400 mg, 840 μmol), tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (320 mg, 1.26 mmol), Pd-PEPPSI-IheptCl (81.7 mg, 84.0 μmol), cesium carbonate (821 mg, 2.52 mmol) in dioxane (10 mL) was degassed and purged with nitrogen (x3) and then mixture stirred at 100 °C for 12 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by reversephase chromatography (0.1% formic acid condition) to give the title compound as a yellow solid (200 mg, 33%). LCMS m / z = 650 [M+H]+.

[0450] Step 3. Synthesis of (rac)-3-(6-fluoro-3-methyl-2-oxo-4-(3,9-diazaspiro[5.5]undecan-3 -yl)-2, 3 -dihydro- lH-benzo[d]imidazol- 1 -yl)- 1 -(4-methoxybenzyl)piperidine-2, 6-dione trifluoroacetate.

[0451] To a solution of tert-butyl (rac)-9-(6-fluoro-l-(l-(4-methoxybenzyl)-2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (200 mg, 308 μmol) in DCM (6 mL) was added TFA (2 mL) and the mixture stirred at 25 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a yellow oil (200 mg, crude). LCMS m / z = 550 [M+H]+.

[0452] Step 4. Synthesis of (rac)-3-(6-fluoro-3-methyl-4-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0453] To a solution of (rac)-3-(6-fluoro-3-methyl-2-oxo-4-(3,9-diazaspiro[5.5]undecan-3-yl)-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione trifluoroacetate (Step 3, 200 mg, 364 μmol) and 5-fluoro-2-nitropyridine (103 mg, 728 μmol) in DMSO (3 mL) was added DIPEA (94.1 mg, 728 μmol) and the mixture stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reverse-phase chromatography (0.1% formic acid condition) to give the title compound as a yellow solid (200 mg, 82%). LCMS m / z = 672 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0454] Step 5. Synthesis of (rac)-3-(4-(9-(6-aminopyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-6-fluoro-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione.

[0455] To a solution of (rac)-3-(6-fluoro-3-methyl-4-(9-(6-nitropyridin-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-l-yl)-l-(4-methoxybenzyl)piperidine-2, 6-dione (Step 4, 200 mg, 298 μmol) in anhydrous THF (6 mL) and DMF (2 mL) was added Pt / V / C (50.0 mg, 298 μmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen several times and the mixture stirred under hydrogen (15 psi) at 20 °C for 3 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give the title compound as a brown oil (200 mg, crude). LCMS m / z = 642 [M+H]+.

[0456] Intermediate 63. 7-((lR,2R)-2-fluorocyclopentyl)-2-((5-formylpyridin-2-yl)amino)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

[0457] A mixture of 2-chloro-7-((lR,2R)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 23, 170 mg, 547 μmol), 6-aminonicotinaldehyde (73.5 mg, 602 μmol), BrettPhos (29.4 mg, 54.7 μmol), BrettPhos Pd G4 (50.4 mg, 54.7 μmol), 4A molecular sieves and KO Ac (537 mg, 5.47 mmol) in dioxane (3 mL) was degassed and purged with nitrogen (x3) and the reaction mixture stirred at 100 °C for 2 h under nitrogen. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (3x 30 mL). The combined organics were dried and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 0-100% EtOAc / PE) to give the title compound as a yellow solid (150 mg, 58%).NMR (400 MHz, CDCh) 8: 9.98 (s, 1H), 8.87 (s, 1H), 8.84-8.75 (m, 2H), 8.60 (d, 1H), 8.20 (dd, 1H), 6.57 (s, 1H), 5.95-5.72 (m, 1H), 5.04-4.85 (m, 1H), 3.19 (s, 6H), 2.55-2.31 (m, 3H), 2.17-1.94 (m, 3H)

[0458] Intermediates 64-72

[0459] The title compounds were prepared from 6-aminonicotinaldehyde and the appropriate chloroheterocycle (ArCl) using an analogous method to that described for Intermediate 59.Attorney Ref. No. 01234-0009-00PCTIntermediate Name / Structure / Amine / Halide / Data64 7-((lS,2S)-2-fluorocyclopentyl)-2-((5-formylpyri din-2 -yl)amino)-N, N- dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideFXX H N N N io oodJ W / ArCl: 2-chloro-7-((lS,2S)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide (Intermediate 24)Yield: 160 mg, 83%; LCMS m / z = 397 [M+H]+.65 7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)- N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((l S,2S,4R)- bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)-N, N-dimethyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide°X N=Z N-Y Y hl0=b N=Z N — ® / x hr X XN f1orX XN / 1ArCl: 7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lS,2S,4R)- bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide (Intermediate 6)Yield: 160 mg, 80%; LCMS m / z = 405 [M+H]+.66 7-((lS,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)- N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2R,4S)- bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)-N, N-dimethyl-7H- pyrrolo[2,3-d]pyrimidine-6-carboxamide°b Xx °b ^xX p1X Xhl 'orhl '1Attorney Ref. No. 01234-0009-00PCTArCl: 7-((lS,2S,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2R,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (Intermediate 7)Yield: 140 mg, 66%; LCMS m / z = 404 [M+H]+.7-((lS,2R,4R)-bicyclo[2.2.1 ]heptan-2-yl)-2-((5-formylpyri din-2 -yl)amino)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide°=\ 0 °=\ 0\, 7 N JIx< 7 0 JI.N=Z N — / Jr fr N=< N— / JrNP1' N forN fArCl: 7-((l S,2R,4R)-bicyclo[2.2. l]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (peak 1, Intermediate 8)Yield: 125 mg, 97%; 'H-NMR (400 MHz, CDC13): 9.96 (s, 1H), 9.32-9.16 (m, 1H), 8.87-8.77 (m, 2H), 8.65 (d, 1H), 8.21 (dd, 1H), 6.51 (s, 1H), 4.50-4.44 (m, 1H), 3.16 (d, 6H), 2.90-2.80 (m, 2H), 2.56 (s, 1H), 2.41 (d, 1H), 1.94-1.82 (m, 1H), 1.72-1.62 (m, 2H), 1.39-1.29 (m, 3H).7-((lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)- N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((l S,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-2-((5-formylpyridin-2-yl)amino)-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide°"b 0 - 0 0,10 y1NorN / ArCl: 7-((lR,2S,4S)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide or 7-((lS,2R,4R)-bicyclo[2.2.1]heptan-2-yl)-2-chloro-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (peak 2, Intermediate 9)Attorney Ref. No. 01234-0009-00PCTYield: 170 mg, 96%; LCMS m / z = 405 [M+H]+.70 7-((lR,2S)-2-fluorocyclopentyl)-2-((5-formylpyridin-2-yl)amino)-N, N- dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide" '~p / ArCl: 2-chloro-7-((lR,2S)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamideYield: 35 mg, 78%; LCMS m / z = 397 [M+H]+.71 7-cyclopropyl-2-((5-formylpyridin-2-yl)amino)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamideH N N N JArCl: 2-chloro-7-cyclopropyl-N, N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6- carboxamide (Intermediate 4)Yield: 190 mg, 67%; LCMS m / z = 351 [M+H]+.72 7-((lS,2R)-2-fluorocyclopentyl)-2-((5-formylpyridin-2-yl)amino)-N, N- dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideF" / jH rN N N io o / ArCl: 2-chloro-7-((lS,2R)-2-fluorocyclopentyl)-N, N-dimethyl-7H-pyrrolo[2,3- d]pyrimidine-6-carboxamide (Intermediate 15)Yield: 90 mg; LCMS m / z = 397 [M+H]+.

[0460] Intermediate 73. (rac)-3-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione.Attorney Ref. No. 01234-0009-00PCT

[0461] Step 1. Synthesis of tert-butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2, 7-di azaspiro [3.5 ] nonane-2-carb oxy 1 ate.

[0462] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (2.00 g, 4.48 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.12 g, 4.93 mmol), RuPhos Pd G3 (449 mg, 537 pmol), cesium carbonate (2.92 g, 8.96 mmol) in dioxane (40 mL) was degassed and purged with nitrogen (3x) at 25 °C and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3x 70 mL). The combined organics were washed with brine (2x 20 mL), dried (Na2SO4) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiCh, 2-25% EtOAc / PE) to give the title compound as an orange solid (2.20 g, 73%). 'H-NMR (400 MHz, DMSO-d6): 7.67 (d, 1H), 7.44-7.27 (m, 12H), 6.94 (d, 2H), 6.51 (d, 1H), 5.37 (d, 4H), 3.58 (s, 4H), 3.13 (s, 4H), 1.75 (t, 4H), 1.38 (s, 9H).

[0463] Step 2. Synthesis of tert-butyl (rac)-7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-di azaspiro [3.5 ] nonane-2-carb oxy 1 ate.

[0464] tert-Butyl 7-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 1, 1.00 g, 1.69 mmol) was added to Pd / C (269 mg, 253 pmol, 10% purity) and Pd(OH)2 (355 mg, 253 pmol, 10% purity) in THF (15 mL) at 30 °C. The reaction mixture was stirred at 30°C for 16 h under hydrogen (15 psi). The reaction mixture was filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 2-50% EtOAc / PE) to afford the title compound as a white solid (600 mg, 85%).[H-NMR (400 MHz, DMSO-d6): 10.76 (s, 1H), 7.03 (d, 2H), 6.88 (d, 2H), 3.71 (dd, 1H), 3.58 (s, 4H), 3.18-3.00 (m, 4H), 2.69-2.56 (m, 1H), 2.48-2.41 (m, 1H), 2.18-2.06 (m, 1H), 2.04-1.95 (m, 1H), 1.75 (t, 4H), 1.38 (s, 9H).

[0465] Step 3. Synthesis of (rac)-3-(4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione trifluoroacetate.Attorney Ref. No. 01234-0009-00PCT

[0466] To a solution of tert-butyl 7-(4-(2,6-dioxopiperidin-3-yl)phenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Step 2, 50.0 mg, 120 pmol) in DCM (1 mL) was added TFA (2.69 mmol, 0.2 mL) and the reaction mixture stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow oil (50.0 mg, 96%).

[0467] Intermediate 74. (rac)-3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione hydrochloride.

[0468] Step 1. Synthesis of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3, 9-diazaspiro[5.5]undecane-3-carboxylate.

[0469] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (1.14 g, 4.48 mmol), cesium carbonate (2.92 g, 8.96 mmol) and RuPhos Pd G3 (375 mg, 448 pmol) in dioxane (30 mL) was degassed and purged with nitrogen (3x) and the mixture stirred at 100 °C for 16 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue diluted with water (50 mL) and extracted with ethyl acetate (3x 50 mL). The combined organics were washed with brine (3x 100 mL), dried (ISfeSCU) and concentrated under reduced pressure. The residue was purified by column chromatography (SiCh, 20% EtOAc / PE) to afford the title compound as a yellow solid (2.78 g, 76%). LCMS m / z = 620 [M+H]+.

[0470] Step 2. Synthesis of tert-butyl (rac)-9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate.

[0471] To a solution of tert-butyl 9-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 1, 2.25 g, 3.63 mmol) in ethanol (15 mL) and ethyl acetate (30 mL) was added Pd / C (600 mg, 564 pmol, 10% purity) and Pd(OH)2 (600 mg, 427 pmol, 10% purity) under nitrogen and the suspension degassed and purged with hydrogen (3x). The reaction mixture was stirred under hydrogen (15 Psi) at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue purified by reverse-phaseAttorney Ref. No. 01234-0009-00PCTchromatography (35% MeCN / FLO (0.1% FA condition)) to give the title compound as a white solid (1.37 g, 76%). LCMS m / z = 442 [M+H]+.

[0472] Step 3. Synthesis of (rac)-3-(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)piperidine-2, 6-dione hydrochloride.

[0473] To a solution of tert-butyl 9-(4-(2,6-dioxopiperidin-3-yl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (Step 2, 500 mg, 1.03 mmol) in DCM (5 mL) was added HCl / dioxane (4 M, 5 mL) and the mixture stirred at 20 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give the title compound as a white solid (390 mg, crude). LCMS m / z = 342 [M+H]+.

[0474] Intermediate 75. (rac)-3-(2,6-difhioro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione trifluoroacetate.

[0475] Step 1. Synthesis of 2, 6-bis(benzyloxy)-3-(4-bromo-2,6-difluorophenyl)pyri dine.

[0476] A solution of 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (3.00 g, 7.19 mmol), 5-bromo-l,3-difluoro-2-iodo-benzene (11.4 g, 35.9 mmol,), XPhos Pd G3 (608 mg, 718 pmol), sodium carbonate (1.52 g, 14.3 mmol), 4A MS (1 g) in dioxane (150 mL) and water (30 mL) was stirred at 40 °C for 3 h under nitrogen. The reaction mixture was concentrated under reduced pressure and the residue purified by reversed-phase HPLC (0.1% formic acid condition) to give title compound as a brown oil (1.80 g, 47%). LCMS m / z = 482 [M+H]+.

[0477] Step 2-4. Synthesis of (rac)-3-(2,6-difluoro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)piperidine-2, 6-dione.

[0478] The title compound was prepared from 2,6-bis(benzyloxy)-3-(4-bromo-2,6-difhiorophenyl)pyridine (Step 1, 1.6 g, 3.32 mmol) and tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (750 mg, 3.32 mmol) using an analogous 3-Step procedure as described for Intermediate 74. LCMS m / z = 350 [M+H]+.Attorney Ref. No. 01234-0009-00PCT

[0479] Intermediate 76. tert-butyl 3 -(6-chloropyri din-3 -yl)-3 -fluoroazetidine- 1-carb oxy late

[0480] Step 1: Synthesis of tert-butyl 3 -(6-chloropyri din-3 -yl)-3-hy droxyazeti dine- 1-carb oxy late

[0481] Solution 1 = 5-bromo-2-chloropyridine (5.0 g, 25.9 mmol) in THF (10 mL)

[0482] Solution 2 = n-butyllithium, (1.6 M, 2.436 mL, 3.9 mmol)

[0483] Solution 3 = tert-butyl 3 -oxoazetidine- 1 -carboxylate (5.3 g, 31.0 mmol) in THF (10 mL)

[0484] Solution 1 was pumped (Pump 1...

Claims

1. Attorney Ref. No. 01234-0009-00PCT2.CLAIMS3.What is claimed is:

1. A compound of Formula (I):

6.

7. or a pharmaceutically acceptable salt thereof, wherein8.R1and R2are each independently selected from H, D, and Ci-C4alkyl;9.R3is selected from Ci-Cealkyl optionally substituted with 1 to 4 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;10.L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, -(C(Ra2)2)P-C*(=O)-, - (C(Ra2)2)P- N(Rd2)C*(=O)-, and -(C(Ra2)2)P-C(=O)N*(Rd2)- wherein * denotes the point of attachment of L1to X1;11.X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;12.L2is selected from a covalent bond, -(C(Ra3)2)P-, -O-, and -C(=O)-;13.X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb3, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4;14.L3is selected from a covalent bond, -O-, and -(C(Ra4)2)P-or15.L3is -C2-C4alkynyl-, provided that X2is a covalent bond or X1- L2- X2form a 5- to 12- membered spiroheterocyclyl or a 6- to 12-membered fused heterocyclyl; or16.L3is selected from -*0-(C(Rel)2)q-C(=0)- and -*N(Rd5)-(C(Rel)2)q-C(=O)-, wherein * denotes the point of attachment of L3to Ring B, provided that X2is a covalent bond; or X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- Attorney Ref. No. 01234-0009-00PCT17.to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd6; or18.X2- L3form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb5, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd7;19.Ring B is selected from:

21.

22. Y1is selected from NRd9and -*N(Rd9)-C(=O)-, wherein * denotes the point of attachment of Y1to W;23.R4is selected from H, D, and Ci-C4alkyl;24.Y2is C(Re)2 or C(=O);25.W is CH or N;26.Ral, Ra2, Ra3, and Ra4are each independently selected from H, D, halo, OH, Ci-C4alkyl, Ci- C4alkoxy, and monocyclic C3-C6 cycloalkyl;27.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic Cs-Cecycloalkyl, or two Rblattached to the same atom, form a =0;28.Rb2, Rb3, Rb4, and Rb5are each independently selected from D, halo, OH, CN, and Ci-C4alkyl, or two Rb2, Rb3, Rb4, or Rb5attached to the same atom, form a =0;29.Rcland Rc2are each independently selected from D, halo, OH, CN, and Ci-C4alkyl;30.Rc3are each independently selected from H, D, halo, OH, CN, and Ci-C4alkyl; Attorney Ref. No. 01234-0009-00PCT31.Rdl, Rd2, Rd3, Rd4, Rd5, Rd6, Rd7, Rd8, Rd9, and Rdl° are each independently selected from H, D, Ci-C4alkyl, and monocyclic Cs-Cecycloalkyl;32.Relare each independently selected from D, halo, OH, CN, N(Rdl0)2, Ci-C4alkyl, and Ci- C4alkoxy;33.Rfland Rf2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; m is 0 or 1;34.n is 0, 1, 2, 3, or 4;35.p is 0, 1, or 2;36.q is 0, 1, or 2; and37.tis 0, 1, or 2;38.provided that:39.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

2. A compound of Formula (II):

42.

43. or a pharmaceutically acceptable salt thereof, wherein44.R1and R2are each independently selected from H, D, and Ci-C4alkyl;45.R3is selected from Ci-Cealkyl optionally substituted with 1 to 4 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRdl;46.L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, -(C(Ra2)2)P-C*(=O)-, -(C(Ra2)2)P- N(Rd2)C*(=O)-, and -(C(Ra2)2)P-C(=O)N*(Rd2)- wherein * denotes the point of attachment of L1to X1;47.X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd3;48.L2is selected from a covalent bond, -(C(Ra3)2)P-, -O-, and -C(=O)-; Attorney Ref. No. 01234-0009-00PCT49.X2is selected from a covalent bond, Cs-Ciocycloalkyl optionally substituted with 1 to 4 Rb3, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd4; or50.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 4 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a - ring carbon with 1 to 4 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 4 ring heteroatoms each independently selected from O, S, N, and NRd6;51.Ring B is selected from:

53.

54. Y1is selected from NRd9and -*N(Rd9)-C(=O)-, wherein * denotes the point of attachment of Y1to W;55.R4is selected from H, D, and Ci-C4alkyl;56.Y2is C(Re)2 or C(=O);57.W is CH or N;58.Ral, Ra2, and Ra3are each independently selected from H, D, halo, OH, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic C3-C6 cycloalkyl;59.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, Ci-C4alkoxy, and monocyclic Cs-Cecycloalkyl, or two Rblattached to the same atom, form a =0; Attorney Ref. No. 01234-0009-00PCT60.Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, CN, and Ci-C4alkyl, or two Rb2, Rb3, or Rb4attached to the same atom, form a =0;61.Rcland Rc2are each independently selected from D, halo, OH, CN, and Ci-C4alkyl;62.Rc3are each independently selected from H, D, halo, OH, CN, and Ci-C4alkyl;63.Rdl, Rd2, Rd3, Rd4, Rd6, Rd8, and Rd9are each independently selected from H, D, Ci-C4alkyl, and monocyclic Cs-Cecycloalkyl;64.Rfland Rf2are each independently selected from H, D, halo, and Ci-C4alkyl; or two Rfltogether with the carbon atom to which they are attached form a monocyclic Cs-Cecycloalkyl; m is 0 or 1;65.n is 0, 1, 2, 3, or 4;66.p is 0, 1, or 2;67.q is 0, 1, or 2; and68.tis 0, 1, or 2;69.provided that:70.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

3. The compound of claim 1, wherein Ring B is selected from:

73.

74. wherein “ * ” indicates the point of attachment to (Y^m Attorney Ref. No. 01234-0009-00PCT4. The compound of claim 1, wherein Ring B is selected from:

77.

78. wherein “ * ” indicates the point of attachment to (Y^m5. The compound of claim 1, wherein the compound is represented by Formula (III):

81.

82. or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5, wherein the compound is represented by Formula (Illa):

85.

86. or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6, wherein the compound is represented by Formula (Illd):

89.

90. or a pharmaceutically acceptable salt thereof, wherein91.R1and R2are each independently selected from H, D, and Ci-C4alkyl; Attorney Ref. No. 01234-0009-00PCT92.R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;93.L1is a covalent bond or -(C(Ra2)2)P-;94.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;95.Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;96.Ra2are each independently selected from H, D, and Ci-C4alkyl;97.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;98.Rb4are each independently selected from D, halo, OH, and CN;99.Rcland Rc2are each independently selected from D, halo, OH, and CN;100.Rdland Rd6are each independently selected from H, D, and Ci-C4alkyl;101.n is 0, 1, 2, or 3; and102.p is 1 or 2;103.provided that:104.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

8. The compound of claim 7, wherein106.R1and R2are each independently selected from H, D, and Ci-Csalkyl;107.R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;108.L1is -(C(Ra2)2)P-;109.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;110.Ra2are each independently selected from H, D, and Ci-Csalkyl;111.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;112.Rb4are each independently selected from D, halo, and OH;113.Rcland Rc2are each independently selected from D, halo, and OH;114.Rd6is selected from H, D, and Ci-Csalkyl;115.n is 0, 1, or 2; and Attorney Ref. No. 01234-0009-00PCT116.p is 1;117.provided that:118.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

9. The compound of claim 1, wherein the compound is represented by Formula (IV):

121.

122. or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9, wherein the compound is represented by Formula (IVb):

125.

126. or a pharmaceutically acceptable salt thereof.

11. The compound of claim 10, wherein the compound is represented by Formula (IVg):

129.

130. or a pharmaceutically acceptable salt thereof, wherein131.R1and R2are each independently selected from H, D, and Ci-C4alkyl;132.R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;133.L1is selected from a covalent bond, -(C(Ra2)2)P-, and -O-;134.X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein Attorney Ref. No. 01234-0009-00PCT135.the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;136.L2is a covalent bond or -(C(Ra3)2)P-;137.X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;138.Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;139.Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;140.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;141.Rb2and Rb3are each independently selected from D, halo, OH, and CN;142.Rcland Rc2are each independently selected from D, halo, OH, and CN;143.Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-C4alkyl;144.n is 0, 1, 2, or 3; and145.p is 1 or 2;146.provided that:147.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

12. The compound of claim 11, wherein149.R1and R2are each independently selected from H, D, and Ci-Csalkyl;150.R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;151.L1is -(C(Ra2)2)P-;152.X1is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;153.L2is a covalent bond;154.X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;155.Ra2are each independently selected from H, D, and Ci-Csalkyl;156.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;157.Rb2and Rb3are each independently selected from D, halo, and OH;158.Rcland Rc2are each independently selected from D, halo, and OH;159.Rd3and Rd4are each independently selected from H, D, and Ci-Csalkyl; Attorney Ref. No. 01234-0009-00PCT160.n is 0, 1, or 2; and161.P is 1;162.provided that:163.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

13. The compound of claim 9, wherein the compound is represented by Formula (IVc):

166.

167. or a pharmaceutically acceptable salt thereof.

14. The compound of claim 13, wherein the compound is represented by Formula (IVh):

170.

171. or a pharmaceutically acceptable salt thereof, wherein172.R1and R2are each independently selected from H, D, and Ci-C4alkyl;173.R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;174.L1is a covalent bond or -(C(Ra2)2)P-;175.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;176.Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;177.Ra2are each independently selected from H, D, and Ci-C4alkyl;178.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy; Attorney Ref. No. 01234-0009-00PCT179.Rb4are each independently selected from D, halo, OH, and CN;180.Rcland Rc2are each independently selected from D, halo, OH, and CN;181.Rdland Rd6are each independently selected from H, D, and Ci-C4alkyl;182.n is 0, 1, 2, or 3; and183.p is 1 or 2;184.provided that:185.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

15. The compound of claim 14, wherein187.R1and R2are each independently selected from H, D, and Ci-Csalkyl;188.R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;189.L1is a covalent bond;190.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;191.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;192.Rb4are each independently selected from D, halo, and OH;193.Rcland Rc2are each independently selected from D, halo, and OH;194.Rd6is selected from H, D, and Ci-Csalkyl;195.n is 0, 1, or 2; and196.P is 1;197.provided that:198.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

16. The compound of claim 1, wherein the compound is represented by Formula (V):200.O202.

203. or a pharmaceutically acceptable salt thereof.

17. The compound of claim 16, wherein the compound is represented by Formula (Vb):Attorney Ref. No. 01234-0009-00PCT206.

207. or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein the compound is represented by Formula (Vf):209.O211. 213.or a pharmaceutically acceptable salt thereof, wherein214.R1and R2are each independently selected from H, D, and Ci-C4alkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;215.R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;216.L1is selected from a covalent bond, -(C(Ra2)2)P-, and -O-;217.X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;218.L2is a covalent bond or -(C(Ra3)2)P-;219.X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4; or Attorney Ref. No. 01234-0009-00PCT220.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;221.Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;222.Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;223.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;224.Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, and CN, or two Rb2, Rb3, or Rb4attached to the same atom, form a =0;225.Rcland Rc2are each independently selected from D, halo, OH, and CN;226.Rdl, Rd3, Rd4, and Rd6are each independently selected from H, D, and Ci-C4alkyl;227.n is 0, 1, 2, or 3; and228.p is 1 or 2;229.provided that:230.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

19. The compound of claim 18, wherein232.R1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;233.R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;234.L1is a covalent bond or -O-;235.X1is selected from Cs-Cscycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 10- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;236.L2is a covalent bond or -(C(Ra3)2)P-;237.X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;238.Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy; Attorney Ref. No. 01234-0009-00PCT239.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;240.Rb2and Rb3are each independently selected from D, halo, and OH;241.Rcland Rc2are each independently selected from D, halo, and OH;242.Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl;243.n is 0, 1, or 2; and244.P is 1;245.provided that:246.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

20. The compound of claim 18, wherein248.R1and R2are each independently selected from H, D, and Ci-Csalkyl, wherein one or more H in Ci-C4alkyl can be replaced by D;249.R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Raland Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;250.L1is a covalent bond;251.X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;252.Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;253.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;254.Rb4are each independently selected from D, halo, and OH, or two Rb4attached to the same atom, form a =0;255.Rcland Rc2are each independently selected from D, halo, and OH;256.Rdland Rd6are each independently selected from H, D, and Ci-Csalkyl; and257.n is 0, 1, or 2;258.provided that:259.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

21. The compound of claim 1, wherein the compound is represented by Formula (VI):Attorney Ref. No. 01234-0009-00PCT262.

263. or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein the compound is represented by Formula (VIb):

266.

267. or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22, wherein the compound is represented by Formula (VIf) or Formula (VIg):

270.

271. or a pharmaceutically acceptable salt thereof, wherein Attorney Ref. No. 01234-0009-00PCT272.R1and R2are each independently selected from H, D, and Ci-C4alkyl;273.R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;274.L1is selected from a covalent bond, -(C(Ra2)2)P-, -O-, and -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;275.X1is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb2and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;276.L2is a covalent bond or -(C(Ra3)2)P-;277.X2is selected from Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rb3and 3- to 12- membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4; or278.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;279.Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;280.Ra2and Ra3are each independently selected from H, D, and Ci-C4alkyl;281.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;282.Rb2, Rb3, and Rb4are each independently selected from D, halo, OH, and CN;283.Rcland Rc2are each independently selected from D, halo, OH, and CN;284.Rdl, Rd3, Rd4, and Rd6are each independently selected from H, D, and Ci-C4alkyl;285.n is 0, 1, 2, or 3; and286.p is 1 or 2;287.provided that:288.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

24. The compound of claim 23, wherein290.R1and R2are each independently selected from H, D, and Ci-Csalkyl; Attorney Ref. No. 01234-0009-00PCT291.R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral, Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;292.L1is a covalent bond;293.X1is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb2, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd3;294.L2is a covalent bond;295.X2is 3- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb3, wherein the 3- to 10-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd4;296.Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;297.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;298.Rb2and Rb3are each independently selected from D, halo, and OH;299.Rcland Rc2are each independently selected from D, halo, and OH;300.Rdl, Rd3, and Rd4are each independently selected from H, D, and Ci-Csalkyl; and301.n is 0, 1, or 2;302.provided that:303.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

25. The compound of claim 24, wherein305.R1and R2are each independently selected from H, D, and Ci-Csalkyl;306.R3is Cs-Cscycloalkyl optionally substituted with 1 to 3 Rbl;307.L1is selected from a covalent bond, -(C(Ra2)2)P-, and -(C(Ra2)2)P-C*(=O)-, wherein * denotes the point of attachment of L1to X1;308.X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;309.Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;310.Rblare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;311.Rb4are each independently selected from D, halo, and OH;312.Rcland Rc2are each independently selected from D, halo, and OH;313.Rdland Rd6are each independently selected from H, D, and Ci-Csalkyl; Attorney Ref. No. 01234-0009-00PCT314.n is 0, 1, or 2; and315.P is 1;316.provided that:317.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

26. The compound of claim 1, wherein the compound is represented by Formula (VII):319.H N N321.

322. or a pharmaceutically acceptable salt thereof.

27. The compound of claim 26, wherein the compound is represented by Formula (Vllb):324.N N326.

327. or a pharmaceutically acceptable salt thereof.

28. The compound of claim 27, wherein the compound is represented by Formula (Vllf):329.N N N331.

332. (Vllf), or a pharmaceutically acceptable salt thereof, wherein333.R1and R2are each independently selected from H, D, and Ci-C4alkyl; Attorney Ref. No. 01234-0009-00PCT334.R3is selected from Ci-Cealkyl optionally substituted with 1 to 3 Ral, Cs-Ciocycloalkyl optionally substituted with 1 to 3 Rbl, and 3- to 12-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rbl, wherein the 3- to 12-membered heterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRdl;335.L1is a covalent bond or -(C(Ra2)2)P-;336.X1- L2- X2form a 5- to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4or a 6- to 12-membered fused heterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5- to 12-membered spiroheterocyclyl and the 6- to 12-membered fused heterocyclyl have 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;337.Ralare each independently selected from D, halo, OH, Ci-C4alkyl, and Ci-C4alkoxy;338.Ra2are each independently selected from H, D, and Ci-C4alkyl;339.Rblare each independently selected from D, halo, OH, CN, Ci-C4alkyl, and Ci-C4alkoxy;340.Rb4are each independently selected from D, halo, OH, and CN;341.Rcland Rc2are each independently selected from D, halo, OH, and CN;342.Rdland Rd6are each independently selected from H, D, and Ci-C4alkyl;343.n is 0, 1, 2, or 3; and344.p is 1 or 2;345.provided that:346.(i) when both R1and R2are methyl and R3is cyclopentyl, then at least one Rblis present.

29. The compound of claim 28, wherein348.R1and R2are each independently selected from H, D, and Ci-Csalkyl;349.R3is selected from Ci-C4alkyl optionally substituted with 1 to 3 Ral;350.L1is a covalent bond;351.X1- L2- X2form a 5 to 12-membered spiroheterocyclyl optionally substituted on a ring carbon with 1 to 3 Rb4, wherein the 5 to 12-membered spiroheterocyclyl has 1 to 3 ring heteroatoms each independently selected from O, S, N, and NRd6;352.Ralare each independently selected from D, halo, OH, Ci-Csalkyl, and Ci-Csalkoxy;353.Rb4are each independently selected from D, halo, and OH;354.Rcland Rc2are each independently selected from D, halo, and OH;355.Rd6is selected from H, D, and Ci-Csalkyl; and356.n is 0, 1, or 2. Attorney Ref. No. 01234-0009-00PCT30. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of any one of claims 1 to 30, and at least one pharmaceutically acceptable excipient.

32. A method of treating a disease or disorder mediated by cyclin-dependent kinase 4 (CDK4), comprising providing to a subject in need thereof the compound or pharmaceutically acceptable salt of any one of claims 1-30 or a pharmaceutical composition of claim 31.

33. The method of claim 32, wherein the disease or disorder mediated by CDK4 is cancer.

34. The method of claim 33, wherein the cancer is selected from bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer, esophageal cancer, gastric cancer, head and neck cancer (e.g., head and neck squamous cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), and prostate cancer.

35. The method of claim 33, wherein the cancer is breast cancer.

36. The method of claim 33, wherein the cancer is prostate cancer.

37. The method of claim 33, wherein the cancer is a refractory cancer.

38. A compound or pharmaceutically acceptable salt of any one of claims 1-30 or a pharmaceutical composition of claim 31 for use in treating a cancer.

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